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Maeng JE, Kim JH, Kim SC, Yun WG, Kwon W, Han Y, Oh DY, Lee SH, Jang JY, Ku JL. Comprehensive molecular analysis of 26 newly established human pancreatic ductal adenocarcinoma cell lines reveals two clusters with variating drug sensitivities. Cancer Cell Int 2025; 25:53. [PMID: 39972450 PMCID: PMC11837577 DOI: 10.1186/s12935-025-03671-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 02/01/2025] [Indexed: 02/21/2025] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a malignant form of cancer with the worst survival rate and an extremely low rate of response to treatments. The development and molecular characterization of pancreatic cancer cell lines (PCCLs) are essential for studying the biology of highly aggressive pancreatic adenocarcinoma. METHODS We applied whole exome sequencing (WES) and RNA-seq to identify molecular characteristics of 26 newly established PCCLs. Eighteen clinically relevant anti-cancer drugs were used to assess highly heterogeneous drug responses across the 26 cell lines. RESULTS We confirmed that common driver mutations of PDAC were well retained in our cell lines through WES analysis. Transcriptomic analysis identified two representative clusters that correlated with responses to certain drugs. By using Moffitt's classification method, the two clusters, C1 and C2, showed comparable expression patterns to "Basal-like" and "Classical" types, respectively. Drug screening results showed varying responses among different cell lines. In our cohort, C2 displayed greater sensitivity to anti-cancer drugs compared to C1. Furthermore, drugs targeting similar molecular pathways exhibited corresponding reactions among cell lines. CONCLUSIONS Our results underscored that transcriptomic features of pancreatic cancer correlate with drug sensitivity rather than with the effects of targeted drugs. Cell lines are useful in vitro model systems for studying the molecular mechanisms of PDAC.
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Affiliation(s)
- Ju Eun Maeng
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea
- Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, 101, Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Jae-Hyeon Kim
- Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, 101, Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Soon-Chan Kim
- Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, 101, Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Won-Gun Yun
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Wooil Kwon
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Youngmin Han
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea
| | - Do-Youn Oh
- Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Korea
| | - Sang Hyub Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.
| | - Ja-Lok Ku
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Korea.
- Laboratory of Cell Biology, Cancer Research Institute, Seoul National University College of Medicine, 101, Daehak-Ro, Jongno-Gu, Seoul, 03080, Korea.
- Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.
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Metzenmacher M, Zaun G, Trajkovic‐Arsic M, Cheung P, Reissig TM, Schürmann H, von Neuhoff N, O'Kane G, Ramotar S, Dodd A, Gallinger S, Muckenhuber A, Knox JJ, Kunzmann V, Horn PA, Hoheisel JD, Siveke JT, Lueong SS. Minimally invasive determination of pancreatic ductal adenocarcinoma (PDAC) subtype by means of circulating cell-free RNA. Mol Oncol 2025; 19:357-376. [PMID: 39478658 PMCID: PMC11792997 DOI: 10.1002/1878-0261.13747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 08/13/2024] [Accepted: 09/26/2024] [Indexed: 02/05/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) comprises two clinically relevant molecular subtypes that are currently determined using tissue biopsies, which are spatially biased and highly invasive. We used whole transcriptome sequencing of 10 plasma samples with tumor-informed subtypes, complemented by proteomic analysis for minimally invasive identification of PDAC subtype markers. Data were validated in independent large cohorts and correlated with treatment response and patient outcome. Differential transcript abundance analyses revealed 32 subtype-specific, protein-coding cell-free RNA (cfRNA) transcripts. The subtype specificity of these transcripts was validated in two independent tissue cohorts comprising 195 and 250 cases, respectively. Three disease-relevant cfRNA-defined subtype markers (DEGS1, KDELC1, and RPL23AP7) that consistently associated with basal-like tumors across all cohorts were identified. In both tumor and liquid biopsies, the overexpression of these markers correlated with poor survival. Moreover, elevated levels of the identified markers were linked to a poor response to systemic therapy and early relapse in resected patients. Our data indicate clinical applicability of cfRNA markers in determining tumor subtypes and monitoring disease recurrence.
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Affiliation(s)
- Martin Metzenmacher
- Department of Medical Oncology, West German Cancer CenterUniversity Hospital EssenGermany
| | - Gregor Zaun
- Department of Medical Oncology, West German Cancer CenterUniversity Hospital EssenGermany
| | - Marija Trajkovic‐Arsic
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, a partnership between German Cabcer Research Center (DKFZ) and University Hospital EssenGermany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital EssenUniversity of Duisburg‐EssenEssenGermany
| | - Phyllis Cheung
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, a partnership between German Cabcer Research Center (DKFZ) and University Hospital EssenGermany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital EssenUniversity of Duisburg‐EssenEssenGermany
| | - Timm M. Reissig
- Department of Medical Oncology, West German Cancer CenterUniversity Hospital EssenGermany
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, a partnership between German Cabcer Research Center (DKFZ) and University Hospital EssenGermany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital EssenUniversity of Duisburg‐EssenEssenGermany
| | - Hendrik Schürmann
- Department of Medical Oncology, West German Cancer CenterUniversity Hospital EssenGermany
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, a partnership between German Cabcer Research Center (DKFZ) and University Hospital EssenGermany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital EssenUniversity of Duisburg‐EssenEssenGermany
| | - Nils von Neuhoff
- Department of Pediatric Hematology and Oncology, Department for Pediatrics IIIUniversity Hospital of EssenGermany
| | - Grainne O'Kane
- PanCuRx Translational Research InitiativeOntario Institute for Cancer ResearchTorontoCanada
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer CentreUniversity Health NetworkTorontoCanada
| | - Stephanie Ramotar
- PanCuRx Translational Research InitiativeOntario Institute for Cancer ResearchTorontoCanada
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer CentreUniversity Health NetworkTorontoCanada
| | - Anna Dodd
- PanCuRx Translational Research InitiativeOntario Institute for Cancer ResearchTorontoCanada
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer CentreUniversity Health NetworkTorontoCanada
| | - Steven Gallinger
- PanCuRx Translational Research InitiativeOntario Institute for Cancer ResearchTorontoCanada
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer CentreUniversity Health NetworkTorontoCanada
| | - Alexander Muckenhuber
- Institute of PathologyTechnical University of MunichGermany
- German Cancer Consortium (DKTK), Partner Site MunichGermany
| | - Jennifer J. Knox
- PanCuRx Translational Research InitiativeOntario Institute for Cancer ResearchTorontoCanada
- Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer CentreUniversity Health NetworkTorontoCanada
| | - Volker Kunzmann
- Department of Internal Medicine II, Medical Oncology, Comprehensive Cancer Center Mainfranken WürzburgUniversity Hospital WürzburgGermany
| | - Peter A. Horn
- Institute for Transfusion MedicineUniversity Hospital of EssenGermany
| | - Jörg D. Hoheisel
- Division of Functional Genome AnalysisGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Jens T. Siveke
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, a partnership between German Cabcer Research Center (DKFZ) and University Hospital EssenGermany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital EssenUniversity of Duisburg‐EssenEssenGermany
| | - Smiths S. Lueong
- German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, a partnership between German Cabcer Research Center (DKFZ) and University Hospital EssenGermany
- Bridge Institute of Experimental Tumor Therapy (BIT) and Division of Solid Tumor Translational Oncology (DKTK), West German Cancer Center, University Hospital EssenUniversity of Duisburg‐EssenEssenGermany
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Broseghini E, Venturi F, Veronesi G, Scotti B, Migliori M, Marini D, Ricci C, Casadei R, Ferracin M, Dika E. Exploring the Common Mutational Landscape in Cutaneous Melanoma and Pancreatic Cancer. Pigment Cell Melanoma Res 2025; 38:e13210. [PMID: 39609109 DOI: 10.1111/pcmr.13210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 10/01/2024] [Accepted: 10/15/2024] [Indexed: 11/30/2024]
Abstract
Cutaneous melanoma (CM) and pancreatic cancer are aggressive tumors whose incidences are rapidly increasing in the last years. This review aims to provide a complete and update description about mutational landscape in CM and pancreatic cancer, focusing on similarities of these two apparently so different tumors in terms of site, type of cell involved, and embryonic origin. The familial forms of CM and pancreatic cancers are often characterized by a common mutated gene, namely CDKN2A. In fact, a germline mutation in CDKN2A gene can be responsible for the development of the familial atypical multiple mole and melanoma syndrome (FAMMM), which is characterized by melanomas and pancreatic cancer development. Sporadic melanoma and pancreatic cancer showed different key-driven genes. The open-access resource cBioPortal has been explored to deepen and investigate the common mutational landscape of these two tumors. We investigated the common mutated genes found in both melanoma and pancreatic cancer with a frequency of at least 5% of tested patients and copy number alterations with a frequency of at least of 3%. Data showed that 18 mutated genes and 3 copy number alterations are present in both melanoma and pancreatic cancers types. Since we found two patients that developed both melanoma and pancreatic cancer, we compared mutation landscape between the two tumors and identified a pathogenic variant in BRCA2 gene. This review gives valuable insights into the genetic underpinnings of melanoma and pancreatic cancer, urging the continued exploration and research of new genetic biomarkers able to identify patients and families at high risk of developing both cancers and to address to screening and to an effective clinical management of the patient.
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Affiliation(s)
| | - Federico Venturi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giulia Veronesi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Biagio Scotti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marina Migliori
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Internal Medicine Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Desy Marini
- Internal Medicine Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Claudio Ricci
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Pancreas and Endocrine Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Riccardo Casadei
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Pancreas and Endocrine Surgery Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Manuela Ferracin
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Emi Dika
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
- Oncologic Dermatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Eyuboglu S, Alpsoy S, Uversky VN, Coskuner-Weber O. Key genes and pathways in the molecular landscape of pancreatic ductal adenocarcinoma: A bioinformatics and machine learning study. Comput Biol Chem 2024; 113:108268. [PMID: 39467488 DOI: 10.1016/j.compbiolchem.2024.108268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is recognized for its aggressive nature, dismal prognosis, and a notably low five-year survival rate, underscoring the critical need for early detection methods and more effective therapeutic approaches. This research rigorously investigates the molecular mechanisms underlying PDAC, with a focus on the identification of pivotal genes and pathways that may hold therapeutic relevance and prognostic value. Through the construction of a protein-protein interaction (PPI) network and the examination of differentially expressed genes (DEGs), the study uncovers key hub genes such as CDK1, KIF11, and BUB1, demonstrating their substantial role in the pathogenesis of PDAC. Notably, the dysregulation of these genes is consistent across a spectrum of cancers, positing them as potential targets for wide-ranging cancer therapeutics. This study also brings to the fore significant genes encoding intrinsically disordered proteins, in particular GPRC5A and KRT7, unveiling promising new pathways for therapeutic intervention. Advanced machine learning techniques were harnessed to classify PDAC patients with high accuracy, utilizing the key genetic markers as a dataset. The Support Vector Machine (SVM) model leveraged the hub genes to achieve a sensitivity of 91 % and a specificity of 85 %, while the RandomForest model notched a sensitivity of 91 % and specificity of 92.5 %. Crucially, when the identified genes were cross-referenced with TCGA-PAAD clinical datasets, a tangible correlation with patient survival rates was discovered, reinforcing the potential of these genes as prognostic biomarkers and their viability as targets for therapeutic intervention. This study's findings serve as a potent testament to the value of molecular analysis in enhancing the understanding of PDAC and in advancing the pursuit for more effective diagnostic and treatment strategies.
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Affiliation(s)
- Sinan Eyuboglu
- Turkish-German University, Molecular Biotechnology, Sahinkaya Caddesi, No. 106, Beykoz, Istanbul 34820, Turkey
| | - Semih Alpsoy
- Turkish-German University, Molecular Biotechnology, Sahinkaya Caddesi, No. 106, Beykoz, Istanbul 34820, Turkey
| | - Vladimir N Uversky
- USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Orkid Coskuner-Weber
- Turkish-German University, Molecular Biotechnology, Sahinkaya Caddesi, No. 106, Beykoz, Istanbul 34820, Turkey.
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5
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Graham S, Dmitrieva M, Vendramini-Costa DB, Francescone R, Trujillo MA, Cukierman E, Wood LD. From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression. Carcinogenesis 2024; 45:801-816. [PMID: 39514554 DOI: 10.1093/carcin/bgae064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/04/2024] [Accepted: 10/02/2024] [Indexed: 11/16/2024] Open
Abstract
This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.
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Affiliation(s)
- Sarah Graham
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States
| | - Mariia Dmitrieva
- Cancer Signaling & Microenvironment Program, M&C Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Lewis Katz School of Medicine, Temple Health, Philadelphia, PA 19111, United States
| | - Debora Barbosa Vendramini-Costa
- Henry Ford Pancreatic Cancer Center, Henry Ford Health, Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, United States
| | - Ralph Francescone
- Henry Ford Pancreatic Cancer Center, Henry Ford Health, Henry Ford Health + Michigan State University Health Sciences, Detroit, MI 48202, United States
| | - Maria A Trujillo
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, United States
| | - Edna Cukierman
- Cancer Signaling & Microenvironment Program, M&C Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Lewis Katz School of Medicine, Temple Health, Philadelphia, PA 19111, United States
| | - Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, School of Medicine, Baltimore, MD 21231, United States
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Netto D, Frizziero M, Foy V, McNamara MG, Backen A, Hubner RA. Systemic Therapy for Metastatic Pancreatic Cancer-Current Landscape and Future Directions. Curr Oncol 2024; 31:5206-5223. [PMID: 39330013 PMCID: PMC11430697 DOI: 10.3390/curroncol31090385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/22/2024] [Accepted: 08/25/2024] [Indexed: 09/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence. A paucity of strong predictive risk factors mean screening programmes are difficult to implement. Historically, a lack of identifiable and actionable driver mutations, coupled with a relatively immunosuppressed tumour microenvironment, has led to a reliance on cytotoxic chemotherapy. The NAPOLI-3 trial has reported data supporting consideration of NALIRIFOX as a new first-line standard of care. Kirsten Rat Sarcoma Virus (KRAS) G12D mutations are present in >90% of all PDAC's; exciting breakthroughs in small molecule inhibitors targeting KRAS G12D may open new modalities of treatment, and therapies targeting multiple KRAS mutations are also in early clinical trials. Although immunotherapy strategies to date have been disappointing, combination with chemotherapy and/or small molecule inhibitors hold promise and warrant further exploration.
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Affiliation(s)
- Daniel Netto
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Melissa Frizziero
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Victoria Foy
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
| | - Mairéad G. McNamara
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Alison Backen
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
| | - Richard A. Hubner
- The Christie NHS Foundation Trust, 550 Wilmslow Road, Manchester M20 4BX, UK
- Division of Cancer Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
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Lee MR, Woo SM, Kim MK, Han S, Park S, Lee WJ, Lee D, Choi SI, Choi W, Yoon K, Chun JW, Kim Y, Kong S. Application of plasma circulating KRAS mutations as a predictive biomarker for targeted treatment of pancreatic cancer. Cancer Sci 2024; 115:1283-1295. [PMID: 38348576 PMCID: PMC11007020 DOI: 10.1111/cas.16104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 01/11/2024] [Accepted: 01/27/2024] [Indexed: 04/12/2024] Open
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in circulating tumor deoxyribonucleic acid (ctDNA) have been reported as representative noninvasive prognostic markers for pancreatic ductal adenocarcinoma (PDAC). Here, we aimed to evaluate single KRAS mutations as prognostic and predictive biomarkers, with an emphasis on potential therapeutic approaches to PDAC. A total of 128 patients were analyzed for multiple or single KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, and G13D) in their tumors and plasma using droplet digital polymerase chain reaction (ddPCR). Overall, KRAS mutations were detected by multiplex ddPCR in 119 (93%) of tumor DNA and 68 (53.1%) of ctDNA, with a concordance rate of 80% between plasma ctDNA and tumor DNA in the metastatic stage, which was higher than the 44% in the resectable stage. Moreover, the prognostic prediction of both overall survival (OS) and progression-free survival (PFS) was more relevant using plasma ctDNA than tumor DNA. Further, we evaluated the selective tumor-suppressive efficacy of the KRAS G12C inhibitor sotorasib in a patient-derived organoid (PDO) from a KRAS G12C-mutated patient using a patient-derived xenograft (PDX) model. Sotorasib showed selective inhibition in vitro and in vivo with altered tumor microenvironment, including fibroblasts and macrophages. Collectively, screening for KRAS single mutations in plasma ctDNA and the use of preclinical models of PDO and PDX with genetic mutations would impact precision medicine in the context of PDAC.
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Affiliation(s)
- Mi Rim Lee
- Department of Cancer Biomedical ScienceNational Cancer Center Graduate School of Cancer Science and PolicyGoyangKorea
- Molecular Imaging Branch, Division of Convergence TechnologyResearch Institute of National Cancer CenterGoyangKorea
| | - Sang Myung Woo
- Department of Cancer Biomedical ScienceNational Cancer Center Graduate School of Cancer Science and PolicyGoyangKorea
- Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer CenterGoyangKorea
- Immuno‐Oncology Branch, Division of Rare and Refractory CenterResearch Institute of National Cancer CenterGoyangKorea
| | - Min Kyeong Kim
- Targeted Therapy Branch, Division of Rare and Refractory CenterResearch Institute of National Cancer CenterGoyangKorea
| | - Sung‐Sik Han
- Department of Cancer Biomedical ScienceNational Cancer Center Graduate School of Cancer Science and PolicyGoyangKorea
- Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer CenterGoyangKorea
| | - Sang‐Jae Park
- Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer CenterGoyangKorea
| | - Woo Jin Lee
- Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer CenterGoyangKorea
- Interventional Medicine Branch, Division of Clinical ResearchResearch Institute of National Cancer CenterGoyangKorea
| | - Dong‐eun Lee
- Biostatistics Collaboration TeamResearch Core Center, National Cancer CenterGoyangKorea
| | - Sun Il Choi
- Department of Cancer Biomedical ScienceNational Cancer Center Graduate School of Cancer Science and PolicyGoyangKorea
- Molecular Imaging Branch, Division of Convergence TechnologyResearch Institute of National Cancer CenterGoyangKorea
- Henan Key Laboratory of Brain Targeted Bio‐Nanomedicine, School of Life Sciences & School of PharmacyHenan UniversityKaifengHenanChina
| | - Wonyoung Choi
- Department of Cancer Biomedical ScienceNational Cancer Center Graduate School of Cancer Science and PolicyGoyangKorea
- Center for Clinical Trials, Hospital, National Cancer CenterGoyangKorea
- Cancer Molecular Biology Branch, Division of Cancer BiologyResearch Institute of National Cancer CenterGoyangKorea
| | - Kyong‐Ah Yoon
- College of Veterinary MedicineKonkuk UniversitySeoulKorea
| | - Jung Won Chun
- Center for Liver and Pancreatobiliary Cancer, Hospital, National Cancer CenterGoyangKorea
- Interventional Medicine Branch, Division of Clinical ResearchResearch Institute of National Cancer CenterGoyangKorea
| | - Yun‐Hee Kim
- Department of Cancer Biomedical ScienceNational Cancer Center Graduate School of Cancer Science and PolicyGoyangKorea
- Molecular Imaging Branch, Division of Convergence TechnologyResearch Institute of National Cancer CenterGoyangKorea
| | - Sun‐Young Kong
- Department of Cancer Biomedical ScienceNational Cancer Center Graduate School of Cancer Science and PolicyGoyangKorea
- Targeted Therapy Branch, Division of Rare and Refractory CenterResearch Institute of National Cancer CenterGoyangKorea
- Department of Laboratory MedicineHospital, National Cancer CenterGoyangKorea
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8
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Elebo N, Abdel-Shafy EA, Cacciatore S, Nweke EE. Exploiting the molecular subtypes and genetic landscape in pancreatic cancer: the quest to find effective drugs. Front Genet 2023; 14:1170571. [PMID: 37790705 PMCID: PMC10544984 DOI: 10.3389/fgene.2023.1170571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 08/29/2023] [Indexed: 10/05/2023] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a very lethal disease that typically presents at an advanced stage and is non-compliant with most treatments. Recent technologies have helped delineate associated molecular subtypes and genetic variations yielding important insights into the pathophysiology of this disease and having implications for the identification of new therapeutic targets. Drug repurposing has been evaluated as a new paradigm in oncology to accelerate the application of approved or failed target-specific molecules for the treatment of cancer patients. This review focuses on the impact of molecular subtypes on key genomic alterations in PDAC, and the progress made thus far. Importantly, these alterations are discussed in light of the potential role of drug repurposing in PDAC.
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Affiliation(s)
- Nnenna Elebo
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, Gauteng, South Africa
- Bioinformatics Unit, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
| | - Ebtesam A. Abdel-Shafy
- Bioinformatics Unit, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
- National Research Centre, Cairo, Egypt
| | - Stefano Cacciatore
- Bioinformatics Unit, International Centre for Genetic Engineering and Biotechnology, Cape Town, South Africa
| | - Ekene Emmanuel Nweke
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, Gauteng, South Africa
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9
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Cassese G, Han HS, Yoon YS, Lee JS, Lee B, Cubisino A, Panaro F, Troisi RI. Role of neoadjuvant therapy for nonmetastatic pancreatic cancer: Current evidence and future perspectives. World J Gastrointest Oncol 2023; 15:911-924. [PMID: 37389109 PMCID: PMC10302990 DOI: 10.4251/wjgo.v15.i6.911] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/17/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is one of the most common and lethal human cancers worldwide. Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC, although only approximately 20% of the patients have resectable tumors when diagnosed. Neoadjuvant chemotherapy (NACT) is recommended for borderline resectable pancreatic cancer. Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology, as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC. In such challenging cases, new potential tools, such as ct-DNA and molecular targeted therapy, are emerging as novel therapeutic options that may improve old paradigms. This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.
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Affiliation(s)
- Gianluca Cassese
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive HPB Surgery and Transplantation Service, Federico II University Hospital, Naples 80131, Italy
| | - Ho-Seong Han
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Yoo-Seok Yoon
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Jun Suh Lee
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Boram Lee
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Antonio Cubisino
- Department of HPB Surgery and Transplantation, Beaujon Hospital, Clichy 92110, France
| | - Fabrizio Panaro
- Department of Digestive Surgery and Liver Transplantation, CHU Montpellier, Montpellier 34100, France
| | - Roberto Ivan Troisi
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive HPB Surgery and Transplantation Service, Federico II University Hospital, Naples 80131, Italy
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10
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Jiao Z, Pan Y, Chen F. The Metabolic Landscape of Breast Cancer and Its Therapeutic Implications. Mol Diagn Ther 2023; 27:349-369. [PMID: 36991275 DOI: 10.1007/s40291-023-00645-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2023] [Indexed: 03/31/2023]
Abstract
Breast cancer is the most common malignant tumor globally as of 2020 and remains the second leading cause of cancer-related death among female individuals worldwide. Metabolic reprogramming is well recognized as a hallmark of malignancy owing to the rewiring of multiple biological processes, notably, glycolysis, oxidative phosphorylation, pentose phosphate pathway, as well as lipid metabolism, which support the demands for the relentless growth of tumor cells and allows distant metastasis of cancer cells. Breast cancer cells are well documented to reprogram their metabolism via mutations or inactivation of intrinsic factors such as c-Myc, TP53, hypoxia-inducible factor, and the PI3K/AKT/mTOR pathway or crosstalk with the surrounding tumor microenvironments, including hypoxia, extracellular acidification and interaction with immune cells, cancer-associated fibroblasts, and adipocytes. Furthermore, altered metabolism contributes to acquired or inherent therapeutic resistance. Therefore, there is an urgent need to understand the metabolic plasticity underlying breast cancer progression as well as to dictate metabolic reprogramming that accounts for the resistance to standard of care. This review aims to illustrate the altered metabolism in breast cancer and its underlying mechanisms, as well as metabolic interventions in breast cancer treatment, with the intention to provide strategies for developing novel therapeutic treatments for breast cancer.
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Affiliation(s)
- Zhuoya Jiao
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350, Longzihu Road, Xinzhan District, Hefei, 230012, China
| | - Yunxia Pan
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350, Longzihu Road, Xinzhan District, Hefei, 230012, China
| | - Fengyuan Chen
- School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, No. 350, Longzihu Road, Xinzhan District, Hefei, 230012, China.
- Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei, China.
- Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, China.
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11
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Mortoglou M, Miralles F, Mould RR, Sengupta D, Uysal-Onganer P. Inhibiting CDK4/6 in pancreatic ductal adenocarcinoma via microRNA-21. Eur J Cell Biol 2023; 102:151318. [PMID: 37105116 DOI: 10.1016/j.ejcb.2023.151318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/17/2023] [Accepted: 04/22/2023] [Indexed: 04/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a 5-year survival rate of 5-10 %. The high mortality rate is due to the asymptomatic progression of clinical features in metastatic stages of the disease, which renders standard therapeutic options futile. PDAC is characterised by alterations in several genes that drive carcinogenesis and limit therapeutic response. The two most common genetic aberrations in PDAC are the mutational activation of KRAS and loss of the tumour suppressor CDK inhibitor 2A (CDKN2A), which culminate the activation of the cyclin-dependent kinase 4 and 6 (CDK4/6), that promote G1 cell cycle progression. Therapeutic strategies focusing on the CDK4/6 inhibitors such as palbociclib (PD-0332991) may potentially improve outcomes in this malignancy. MicroRNAs (miRs/miRNAs) are small endogenous non-coding RNA molecules associated with cellular proliferation, invasion, apoptosis, and cell cycle. Primarily, miR-21 promotes cell proliferation and a higher proportion of PDAC cells in the S phase, while knockdown of miR-21 has been linked to cell cycle arrest at the G2/M phase and inhibition of cell proliferation. In this study, using a CRISPR/Cas9 loss-of-function screen, we individually silenced the expression of miR-21 in two PDAC cell lines and in combination with PD-0332991 treatment, we examined the synergetic mechanisms of CDK4/6 inhibitors and miR-21 knockouts (KOs) on cell survival and death. This combination reduced cell proliferation, cell viability, increased apoptosis and G1 arrest in vitro. We further analysed the mitochondrial respiration and glycolysis of PDAC cells; then assessed the protein content of these cells and revealed numerous Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with PD-0332991 treatment and miR-21 knocking out. Our results demonstrate that combined targeting of CDK4/6 and silencing of miR-21 represents a novel therapeutic strategy in PDAC.
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Affiliation(s)
- Maria Mortoglou
- Cancer Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, W1W 6UW London, UK
| | - Francesc Miralles
- Centre of Biomedical Education/Molecular and Clinical Sciences, Cell Biology Research Centre, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK
| | - Rhys Richard Mould
- Research Centre for Optimal Health, School of Life Sciences, University of Westminster, W1W 6UW London, UK
| | - Dipankar Sengupta
- Health Data Sciences Research Group, Research Centre for Optimal Health, School of Life Sciences, University of Westminster, W1W 6UW London, UK
| | - Pinar Uysal-Onganer
- Cancer Mechanisms and Biomarkers Research Group, School of Life Sciences, University of Westminster, W1W 6UW London, UK.
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Kumarasamy V, Frangou C, Wang J, Wan Y, Dynka A, Rosenheck H, Dey P, Abel EV, Knudsen ES, Witkiewicz AK. Pharmacologically targeting KRAS G12D in PDAC models: tumor cell intrinsic and extrinsic impact. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.18.533261. [PMID: 37162905 PMCID: PMC10168422 DOI: 10.1101/2023.03.18.533261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which new therapeutic interventions are needed. Here we assessed the cellular response to pharmacological KRAS inhibition, which target the central oncogenic factor in PDAC. In a panel of PDAC cell lines, pharmaceutical inhibition of KRAS G12D allele, with MRTX1133 yields variable efficacy in the suppression of cell growth and downstream gene expression programs in 2D culture. CRISPR screens identify new drivers for enhanced therapeutic response that regulate focal adhesion and signaling cascades, which were confirmed by gene specific knockdowns and combinatorial drug synergy. Interestingly, MRTX1133 is considerably more efficacious in the context of 3D cell cultures and in vivo PDAC patient-derived xenografts. In syngeneic models, KRAS G12D inhibition elicits potent tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicates that MRTX1133 activates interferon-γ signaling and induces antigen presentation that modulate the tumor microenvironment. Further investigation on the immunological response using single cell sequencing and multispectral imaging reveals that tumor regression is associated with suppression of neutrophils and influx of effector CD8 + T-cells. Thus, both tumor cell intrinsic and extrinsic events contribute to response and credential KRAS G12D inhibition as promising strategy for a large percentage of PDAC tumors.
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13
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Fang YT, Yang WW, Niu YR, Sun YK. Recent advances in targeted therapy for pancreatic adenocarcinoma. World J Gastrointest Oncol 2023; 15:571-595. [PMID: 37123059 PMCID: PMC10134207 DOI: 10.4251/wjgo.v15.i4.571] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/11/2022] [Accepted: 03/16/2023] [Indexed: 04/12/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%–90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC – erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.
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Affiliation(s)
- Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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14
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Petersen JM, Jhala DN. Compliance with the Current NCCN Guidelines and Its Critical Role in Pancreatic Adenocarcinoma. Lab Med 2023; 54:e1-e9. [PMID: 35706071 DOI: 10.1093/labmed/lmac046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVES Since 2019, the National Comprehensive Cancer Network (NCCN) has recommended genetic testing for patients diagnosed with pancreatic adenocarcinoma that includes universal germline testing and tumor gene profiling for metastatic, locally advanced, or recurrent disease. However, testing compliance with this guideline has not yet been published in the English literature. METHODS A quality assurance/quality improvement retrospective review was done to identify patients diagnosed with pancreatic adenocarcinoma from January 2019 to February 2021 to include the patient's clinical status and genetic test results. RESULTS There were 20 patient cases identified with pancreatic adenocarcinoma. A total of 11 cases had molecular tumor gene profiling and microsatellite instability/mismatch repair (MSI/MMR) testing performed and 1 case had only MSI/MMR testing by immunohistochemistry performed. Only 3 patients of the 20 in total received germline testing. CONCLUSION There was a significant number of patients for whom tumor gene profiling or germline testing had never been attempted as per recommended NCCN guidelines.
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Affiliation(s)
- Jeffrey M Petersen
- Corporal Michael J Crescenz Veteran Affairs Medical Center, Philadelphia, Pennsylvania, USA
- University of Pennsylvania Philadelphia, Pennsylvania, USA
| | - Darshana N Jhala
- Corporal Michael J Crescenz Veteran Affairs Medical Center, Philadelphia, Pennsylvania, USA
- University of Pennsylvania Philadelphia, Pennsylvania, USA
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15
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Badheeb M, Abdelrahim A, Esmail A, Umoru G, Abboud K, Al-Najjar E, Rasheed G, Alkhulaifawi M, Abudayyeh A, Abdelrahim M. Pancreatic Tumorigenesis: Precursors, Genetic Risk Factors and Screening. Curr Oncol 2022; 29:8693-8719. [PMID: 36421339 PMCID: PMC9689647 DOI: 10.3390/curroncol29110686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/09/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant and aggressive tumor. Despite medical advancement, the silent nature of PC results in only 20% of all cases considered resectable at the time of diagnosis. It is projected to become the second leading cause in 2030. Most pancreatic cancer cases are diagnosed in the advanced stages. Such cases are typically unresectable and are associated with a 5-year survival of less than 10%. Although there is no guideline consensus regarding recommendations for screening for pancreatic cancer, early detection has been associated with better outcomes. In addition to continued utilization of imaging and conventional tumor markers, clinicians should be aware of novel testing modalities that may be effective for early detection of pancreatic cancer in individuals with high-risk factors. The pathogenesis of PC is not well understood; however, various modifiable and non-modifiable factors have been implicated in pancreatic oncogenesis. PC detection in the earlier stages is associated with better outcomes; nevertheless, most oncological societies do not recommend universal screening as it may result in a high false-positive rate. Therefore, targeted screening for high-risk individuals represents a reasonable option. In this review, we aimed to summarize the pathogenesis, genetic risk factors, high-risk population, and screening modalities for PC.
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Affiliation(s)
- Mohamed Badheeb
- Internal Medicine Department, College of Medicine, Hadhramout University, Mukalla 50512, Yemen
| | | | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Correspondence: (A.E.); (M.A.)
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Karen Abboud
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ebtesam Al-Najjar
- Faculty of Medicine and Health Sciences, University of Science and Technology, Sana’a 15201, Yemen
| | - Ghaith Rasheed
- Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan
| | | | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Weill Cornell Medical College, New York, NY 14853, USA
- Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Correspondence: (A.E.); (M.A.)
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16
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Fantin A, Gruppo M, De Simoni O, Lonardi S, Cristofori C, Morbin T, Peserico G, Grillo S, Masier A, Franco M, Pilati P, Guzzinati S, Zorzi M, Rugge M. Impact of Microscopic Confirmation on Therapeutic Management of Pancreatic Cancer Patients: Lessons from an Italian Regional Tumor Registry. Cancers (Basel) 2022; 14:5372. [PMID: 36358790 PMCID: PMC9658973 DOI: 10.3390/cancers14215372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/28/2022] [Accepted: 10/28/2022] [Indexed: 11/06/2022] Open
Abstract
Background: Incidence of pancreatic cancer (PC) is increasing worldwide and is set to become the second leading cause of cancer-related death in 2040 with a poor 5-year overall survival (OS). The aim of this study was to analyze the impact of microscopic diagnosis of PC (MiDPC) on diagnostic−therapeutic management and outcome. Methods: The Veneto region (north-eastern Italy) has been covered by a cancer registry (CR) since 1987. Clinical and oncological data about all cases of PC in the Veneto region from 1987 were extracted from the Veneto CR database. Results: In 2018, 1340 incident cases of PC in the Veneto population were registered (4.1% of all malignant tumors), with an increasing trend in females and stable incidence in males. Five-year OS in patients with PC was 8%. The percentage of MiDPC increased from 44% in 2010 to 60% in 2018 (p = 0.001). MiDPC was higher among patients aged < 75 years old (84.4%) compared to those aged ≥75 years old (38.9%), p = 0.001. Between 2010 and 2018, a significant increase in biopsy on the primary neoplasm (24.9% vs. 13%, p < 0.001) was reported. Patients with MiDPC had higher 5-year survival than patients with no MiDPC (12.9% vs. 1.2%, p < 0.001). Conclusions: The implementation of MiDPC was essential to improve diagnostic−therapeutic pathways and consequently the survival of PC patients.
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Affiliation(s)
- Alberto Fantin
- Department of Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Mario Gruppo
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Ottavia De Simoni
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Sara Lonardi
- Medical Oncology Unit 3, Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Chiara Cristofori
- Department of Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Tiziana Morbin
- Department of Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Giulia Peserico
- Department of Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Sabina Grillo
- Department of Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Annalisa Masier
- Department of Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Monica Franco
- Department of Gastroenterology, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Pierluigi Pilati
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | | | - Manuel Zorzi
- Veneto Tumor Registry, Azienda Zero, 35128 Padua, Italy
| | - Massimo Rugge
- Veneto Tumor Registry, Azienda Zero, 35128 Padua, Italy
- Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padua, 35128 Padua, Italy
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Emelyanova M, Pudova E, Khomich D, Krasnov G, Popova A, Abramov I, Mikhailovich V, Filipenko M, Menshikova S, Tjulandin S, Pokataev I. Platinum-based chemotherapy for pancreatic cancer: impact of mutations in the homologous recombination repair and Fanconi anemia genes. Ther Adv Med Oncol 2022; 14:17588359221083050. [PMID: 35309086 PMCID: PMC8928350 DOI: 10.1177/17588359221083050] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Accepted: 01/31/2022] [Indexed: 12/24/2022] Open
Abstract
Background Mutations in homologous recombination (HR) and Fanconi anemia (FA) genes may predispose to pancreatic cancer (PC) and enable the prediction of sensitivity to platinum-based chemotherapy. FOLFIRINOX is a standard treatment option for non-selected PC patients and could be effective due to undiagnosed DNA repair deficiency. Here, we aimed to determine the frequency of mutations in genes involved in the HR and FA pathways, evaluate their clinical implications, and determine the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of PC patients treated with platinum. Methods We performed targeted DNA sequencing of 30 genes (ABRAXAS1, ATM, ATR, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDKN2A, CHEK1, CHEK2, FANCC, FANCF, FANCG, FANCI, FANCL, FANCM, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, RAD52, RAD54B, RBBP8, RINT1, SLX4, and XRCC2) for 543 PC patients. Results In BRCA/PALB2-mutated patients with advanced PC (33 patients, 6.1%), the PFS and OS were higher for first-line platinum therapy than for non-platinum therapy [PFS: HR = 0.28, 95% confidence interval (CI) = 0.10-0.81, p = 0.02; OS: HR = 0.31, 95% CI = 0.08-1.16, p = 0.08]. Among 93 patients (17.1%) with mutations in other HR/FA genes, no statistically significant difference in PFS and OS was observed between first-line platinum therapy and non-platinum therapy (PFS: HR = 0.83, 95% CI = 0.43-1.62, p = 0.59; OS: HR = 0.58, 95% CI = 0.28-1.22, p = 0.15). For patients with early PC, no prognostic value was observed for BRCA1/2, PALB2, or other HR/FA genes mutations. Moreover, a personal history of breast, ovarian, pancreatic, or prostate cancer was identified as the only independent predictor of the risk of BRCA/PALB2 mutations (HR = 5.83, 95% CI = 2.16-15.73, p < 0.01). Conclusion Mutations in the BRCA1/2 and PALB2 genes increase the sensitivity of PC to platinum agents. Thus, alterations in these genes in PC patients must be determined prior to anticancer therapy.
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Affiliation(s)
- Marina Emelyanova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russian Federation
| | - Elena Pudova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
| | - Darya Khomich
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
| | - George Krasnov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
| | - Anna Popova
- N.N. Blokhin National Medical Research Center for Oncology, Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Ivan Abramov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
| | - Vladimir Mikhailovich
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation
| | - Maxim Filipenko
- Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation
| | | | - Sergey Tjulandin
- N.N. Blokhin National Medical Research Center for Oncology, Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Ilya Pokataev
- N.N. Blokhin National Medical Research Center for Oncology, Ministry of Health of the Russian Federation, Moscow, Russian Federation
- City Clinical Cancer Hospital No. 1, Moscow Department of Health, Moscow, Russian Federation
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18
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Yin L, Wei J, Lu Z, Huang S, Gao H, Chen J, Guo F, Tu M, Xiao B, Xi C, Zhang K, Li Q, Wu J, Gao W, Jiang K, Yu J, Miao Y. Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China. JAMA Netw Open 2022; 5:e2148721. [PMID: 35171259 PMCID: PMC8851306 DOI: 10.1001/jamanetworkopen.2021.48721] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
IMPORTANCE A higher incidence of pancreatic cancer has been reported in the Chinese population compared with the White population, but genetic differences are unknown to date. Large-sample germline testing for both familial and sporadic pancreatic cancers has been conducted predominantly in White populations, whereas similar studies in Chinese populations are limited. OBJECTIVE To assess the prevalence of germline sequence variations in patients with pancreatic diseases in China. DESIGN, SETTING, AND PARTICIPANTS This genetic association study was a case series that included genetic data from patients with pancreatic ductal adenocarcinoma (PDAC) or non-PDAC pancreatic diseases seen at The First Affiliated Hospital of Nanjing Medical University in Nanjing, China, between January 2006 and December 2017 (Nanjing cohort). Comparator group data were obtained for a US cohort from Johns Hopkins Hospital (JHH), a population from East Asia from the Exome Aggregation Consortium (ExAC) database, and the larger population from China from the ChinaMAP database. Data were updated and analyzed in July 2021. MAIN OUTCOMES AND MEASURES Next-generation sequencing technology was used to examine the prevalence of deleterious variations in 59 genes of the included Chinese patients with DNA extracted from peripheral blood samples. The Fisher exact test was used to assess differences among the frequencies of germline variations in the study patients vs the comparator groups. RESULTS A total of 1009 patients with PDAC (627 [62.1%] male; mean [SD] age, 62.8 [10.2] years) and 885 with non-PDAC diseases (477 [53.9%] male; mean [SD] age, 52.0 [15.9] years) from the Nanjing cohort were included for genetic analysis; all were Han Chinese individuals. Pathogenic variations were detected in 63 patients with PDAC (6.2%; 95% CI, 4.7%-7.7%). Variations in BRCA2 (odds ratio [OR], 3.2; 95% CI, 1.4-7.7; P = .008) and PALB2 (OR, 5.2; 95% CI, 1.6-17.0; P = .007) were significantly associated with pancreatic risk in the Nanjing cohort. Pathogenic variants of genes associated with homologous recombination DNA damage repair, including ATM, BRCA1/2, PALB2, BRIP1, FANCA, FANCC, RAD51D, and XRCC2, were found in 34 patients with PDAC (3.4%). No Ashkenazi Jewish-specific BRCA2 variation (p.Ser1982fs) was detected. The odds ratio of a SPINK1 variation in patients with PDAC was 3.2 (95% CI, 1.8-5.7; P < .001) in the Nanjing cohort compared with the ExAC cohort. Variations in the pancreatic secretory enzyme genes CPA1 and CPB1 were not detected in the Nanjing cohort. CONCLUSIONS AND RELEVANCE In this genetic association study, sporadic pancreatic cancer was associated with pathogenic germline variations in a cohort from China. These findings provide insights into the genetic background of pancreatic cancer in the Han Chinese population with PDAC.
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Affiliation(s)
- Lingdi Yin
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Jishu Wei
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Zipeng Lu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Shimeng Huang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Hao Gao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Jianmin Chen
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Feng Guo
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Min Tu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Bin Xiao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Chunhua Xi
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Kai Zhang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Qiang Li
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Junli Wu
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Wentao Gao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Kuirong Jiang
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
| | - Jun Yu
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Pancreatic Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, Maryland
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Yi Miao
- Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Pancreas Institute of Nanjing Medical University, Nanjing, China
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19
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Opitz FV, Haeberle L, Daum A, Esposito I. Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia. Cancers (Basel) 2021; 13:cancers13246188. [PMID: 34944807 PMCID: PMC8699458 DOI: 10.3390/cancers13246188] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive neoplasm with a poor survival rate. This is mainly due to late detection, which substantially limits therapy options. A better understanding of the early phases of pancreatic carcinogenesis is fundamental for improving patient prognosis in the future. In this article, we focused on the tumor microenvironment (TME), which provides the biological niche for the development of PDAC from its most common precursor lesions, PanIN (pancreatic intraepithelial neoplasias). Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression.
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20
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Digiacomo G, Volta F, Garajova I, Balsano R, Cavazzoni A. Biological Hallmarks and New Therapeutic Approaches for the Treatment of PDAC. Life (Basel) 2021; 11:life11080843. [PMID: 34440587 PMCID: PMC8400856 DOI: 10.3390/life11080843] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/04/2021] [Accepted: 08/13/2021] [Indexed: 12/27/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest solid tumors and is estimated to become a leading cause of cancer-related death in coming years. Despite advances in surgical approaches and the emergence of new chemotherapy options, its poor prognosis has not improved in the last decades. The current treatment for PDAC is the combination of cytotoxic chemotherapy agents. However, PDAC shows resistance to many antineoplastic therapies with rapid progression. Although PDAC represents a heterogeneous disease, there are common alterations including oncogenic mutations of KRAS, and the frequent inactivation of different cell cycle regulators including the CDKN2A tumor suppressor gene. An emerging field of investigation focuses on inhibiting the function of proteins that suppress the immune checkpoint PD-1/PD-L1, with activation of the endogenous immune response. To date, all conventional immunotherapies have been less successful in patients with PDAC compared to other tumors. The need for new targets, associated with an extended molecular analysis of tumor samples could give new pharmacological options for the treatment of PDAC. It is, therefore, important to push for a broader molecular approach in PDAC research. Here, we provide a selected summary of emerging strategy options for targeting PDAC using CDK4/6 inhibitors, RAS inhibitors, and new drug combinations with immune checkpoint agents.
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Affiliation(s)
- Graziana Digiacomo
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
- Correspondence: ; Tel.: +39-0521-903965
| | - Francesco Volta
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy; (I.G.); (R.B.)
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy; (I.G.); (R.B.)
| | - Andrea Cavazzoni
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
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21
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Crowley F, Park W, O'Reilly EM. Targeting DNA damage repair pathways in pancreas cancer. Cancer Metastasis Rev 2021; 40:891-908. [PMID: 34403012 DOI: 10.1007/s10555-021-09983-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 07/30/2021] [Indexed: 02/07/2023]
Abstract
Pancreas ductal adenocarcinoma (PDAC) is the third most common cause of cancer death in the USA. While other cancers with historically poor prognoses have benefited from new immunotherapies and targeted agents, the 5-year survival rate for PDAC patients has remained static. The accessibility to genomic testing has improved in recent years, and it is now clear that PDAC is a heterogenous disease, with a subset of patients harboring actionable mutations. There are several targeted therapies approved by the Food and Drug administration (FDA) in PDAC: EGFR inhibitor erlotinib (combined with gemcitabine) in unselected patients, TRK inhibitors larotrectinib and entrectinib for patients with NTRK fusion mutation, the PD-1 inhibitor pembrolizumab for mismatch repair-deficient patients, and the poly-ADP-ribose polymerase (PARP) inhibitor olaparib in patients with germline BRCA mutation as a maintenance therapy. DNA damage repair (DDR) is paramount to genomic integrity and cell survival. The defective repair of DNA damage is one of the hallmarks of cancer, and abnormalities in DDR pathways are closely linked with the development of malignancies and upregulation of these pathways linked with resistance to treatment. The prevalence of somatic and germline mutations in DDR pathways in metastatic PDAC is reported to be approximately 15-25%. Patients with DDR gene alterations benefit from a personalized approach to treatment. Recently, the POLO trial demonstrated a progression-free survival (PFS) benefit in metastatic PDAC patients with a germline BRCA1/2 mutation treated with maintenance olaparib following platinum-based induction chemotherapy. This was the first phase 3 randomized trial to establish a biomarker-driven approach in the treatment of PDAC and establishes a precedent for maintenance therapy in PDAC. The review herein aims to outline the current treatment landscape for PDAC patients with DDR gene-mutated tumors, highlight novel therapeutic approaches focused on surmounting tumor resistance, and explore new strategies which may lead to an expansion in the number of patients who benefit from these targeted treatments.
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Affiliation(s)
- Fionnuala Crowley
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY, USA.,Internal Medicine, Mount Sinai Morningside West Hospital Center, New York, NY, USA.,Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Wungki Park
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY, USA.,David M. Rubenstein Center for Pancreas Research, New York, NY, USA.,Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.,Weill Cornell Medical College, New York, NY, USA
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, Office 1021, New York, NY, USA. .,David M. Rubenstein Center for Pancreas Research, New York, NY, USA. .,Weill Cornell Medical College, New York, NY, USA.
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22
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Serum miRNA Profiling for Early PDAC Diagnosis and Prognosis: A Retrospective Study. Biomedicines 2021; 9:biomedicines9070845. [PMID: 34356909 PMCID: PMC8301411 DOI: 10.3390/biomedicines9070845] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/29/2021] [Accepted: 07/15/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Tumor stage predicts pancreatic cancer (PDAC) prognosis, but prolonged and short survivals have been described in patients with early-stage tumors. Circulating microRNA (miRNA) are an emerging class of suitable biomarkers for PDAC prognosis. Our aim was to identify whether serum miRNA signatures predict survival of early-stage PDAC. Methods: Serum RNA from archival 15 stage I-III PDAC patients and 4 controls was used for miRNAs expression profile (Agilent microarrays). PDAC patients with comparable age, gender, diabetes, jaundice and surgery were classified according to survival: less than 14 months (7/15 pts, group A) and more than 22 months (8/15 pts, group B). Bioinformatic data analysis was performed by two-class Significance Analysis of Microarray (SAM) algorithm. Binary logistic regression analyses considering PDAC diagnosis and outcome as dependent variables, and ROC analyses were also performed. Results: 2549 human miRNAs were screened out. At SAM, 76 differentially expressed miRNAs were found among controls and PDAC (FDR = 0.4%), the large majority (50/76, 66%) of them being downregulated in PDAC with respect to controls. Six miRNAs were independently correlated with early PDAC, and among these, hsa-miR-6821-5p was associated with the best ROC curve area in distinguishing controls from early PDAC. Among the 71 miRNAs differentially expressed between groups A and B, the most significant were hsa-miR-3135b expressed in group A only, hsa-miR-6126 and hsa-miR-486-5p expressed in group B only. Eight miRNAs were correlated with the presence of lymph-node metastases; among these, hsa-miR-4669 is of potential interest. hsa-miR-4516, increased in PDAC and found as an independent predictor of survival, has among its putative targets a series of gens involved in key pathways of cancer progression and dissemination, such as Wnt and p53 signalling pathways. Conclusions: A series of serum miRNAs was identified as potentially useful for the early diagnosis of PDAC, and for establishing a prognosis.
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23
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Kurosaki H, Nakatake M, Sakamoto T, Kuwano N, Yamane M, Ishii K, Fujiwara Y, Nakamura T. Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD/UPRT against Pancreatic Ductal Adenocarcinoma in Mice. Cells 2021; 10:cells10050985. [PMID: 33922406 PMCID: PMC8145488 DOI: 10.3390/cells10050985] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/14/2021] [Accepted: 04/20/2021] [Indexed: 02/07/2023] Open
Abstract
Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, MDRVV is more attenuated in normal cells and can replicate in cancer cells that exhibit constitutive ERK1/2 activation in the MAPK pathway. We armed MDRVV with a bifunctional fusion gene encoding cytosine deaminase and uracil phosphoribosyltransferase (CD/UPRT), which converts 5-fluorocytosine (5-FC) into chemotherapeutic agents, and evaluated its oncolytic activity alone or in combination with 5-FC in human pancreatic cancer cell lines, tumor mouse models of peritoneal dissemination and liver metastasis, and ex vivo-infected live pancreatic cancer patient-derived tissues. CD/UPRT-armed MDRVV alone could efficiently eliminate pancreatic cancers, and its antitumor effects were partially enhanced in combination with 5-FC in vitro and in vivo. Moreover, the replication of MDRVV was detected in tumor cells of patient-derived, surgically resected tissues, which showed enlarged nuclei and high expression of pERK1/2 and Ki-67, and not in stromal cells. Our findings suggest that systemic injections of CD/UPRT-armed MDRVV alone or in combination with 5-FC are promising therapeutic strategies for pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Hajime Kurosaki
- Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (H.K.); (M.N.); (N.K.); (M.Y.); (K.I.)
| | - Motomu Nakatake
- Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (H.K.); (M.N.); (N.K.); (M.Y.); (K.I.)
| | - Teruhisa Sakamoto
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan; (T.S.); (Y.F.)
| | - Nozomi Kuwano
- Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (H.K.); (M.N.); (N.K.); (M.Y.); (K.I.)
| | - Masato Yamane
- Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (H.K.); (M.N.); (N.K.); (M.Y.); (K.I.)
| | - Kenta Ishii
- Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (H.K.); (M.N.); (N.K.); (M.Y.); (K.I.)
| | - Yoshiyuki Fujiwara
- Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan; (T.S.); (Y.F.)
| | - Takafumi Nakamura
- Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan; (H.K.); (M.N.); (N.K.); (M.Y.); (K.I.)
- Correspondence: ; Tel.: +81-859-38-7550; Fax: +81-859-38-6422
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24
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Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology. Cancers (Basel) 2021; 13:cancers13040799. [PMID: 33672917 PMCID: PMC7918504 DOI: 10.3390/cancers13040799] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/05/2021] [Accepted: 02/10/2021] [Indexed: 02/06/2023] Open
Abstract
Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes.
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25
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Borchardt H, Ewe A, Morawski M, Weirauch U, Aigner A. miR24-3p activity after delivery into pancreatic carcinoma cell lines exerts profound tumor-inhibitory effects through distinct pathways of apoptosis and autophagy induction. Cancer Lett 2021; 503:174-184. [PMID: 33508384 DOI: 10.1016/j.canlet.2021.01.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 01/18/2021] [Accepted: 01/19/2021] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer is among the most detrimental tumors, with novel treatment options urgently needed. The pathological downregulation of a miRNA in tumors can lead to the overexpression of oncogenes, thus suggesting miRNA replacement as novel strategy in cancer therapy. While the role of miR24 in cancer, including pancreatic carcinoma, has been described as ambiguous, it may hold great promise and deserves further studies. Here, we comprehensively analyze the effects of miR24-3p replacement in a set of pancreatic carcinoma cell lines. Transfection of miR24-3p mimics leads to profound cell inhibition in various 2D and 3D cell assays, based on the induction of apoptosis, autophagy and ROS. Comprehensive analyses of miR24-3p effects on the molecular level reveal the transcriptional regulation of several important oncogenes and oncogenic pathways. Based on these findings, miRNA replacement therapy was preclinically explored by treating tumor xenograft-bearing mice with miR24-3p mimics formulated in polymeric nanoparticles. The obtained tumor inhibition was associated with the induction of apoptosis and necrosis. Taken together, we identify miR24-3p as powerful tumor-inhibitory miRNA for replacement therapy, and describe a complex network of oncogenic pathways affected by miR24.
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Affiliation(s)
- Hannes Borchardt
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, Germany
| | - Alexander Ewe
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, Germany
| | - Markus Morawski
- Paul Flechsig Institute of Brain Research, Faculty of Medicine, University of Leipzig, Germany
| | - Ulrike Weirauch
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, Germany
| | - Achim Aigner
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, Germany.
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26
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Liu S, Zhao S, Dong Y, Wang T, Niu X, Zhao L, Wang G. Antitumor activity and mechanism of resistance of the novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer. Cancer Chemother Pharmacol 2021; 87:415-423. [PMID: 33392641 DOI: 10.1007/s00280-020-04210-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 11/24/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. The benefit of chemotherapy treatment for pancreatic cancer is very limited. Therefore, new therapeutic targets and approaches are urgently needed for this deadly disease. Multi-target therapy is a potential and feasible treatment strategy. Given the important roles that histone deacetylases (HDACs) and phosphoinositide-3-kinase (PI3K) play in pancreatic cancer, we investigated the antitumor activity and mechanism of novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer. METHODS AND RESULTS MTT assay and flow cytometric analysis were used to examine the in vitro antitumor activity of CUDC-907. A BxPC-3-derived xenograft mouse model was used to determine CUDC-907 in vivo efficacy. The TUNEL assay as used to determine apoptosis in tumors in vivo post CUDC-907 treatment. Western blots were used to determine the effect of CUDC-907 on protein levels. Our results show that CUDC-907 decreased viable cells and induced cell death in a concentration-dependent manner. Furthermore, CUDC-907 showed promising in vivo antitumor activity in the BxPC-3-derived xenograft mouse model while exhibiting tolerable toxicity. Furthermore, long-term treatment with CUDC-907 induced phosphorylation of AKT, S6 (ribosomal protein S6), and ERK (extracellular regulated protein kinase), and inhibition of PI3K (phosphatidylinositol 3-kinase), mTOR (mammalian target of rapamycin), or ERK significantly enhanced CUDC-907-induced cell death in pancreatic cell lines. CONCLUSION Taken together, these findings support the clinical development of CUDC-907 for the treatment of pancreatic cancer and identify compensatory activation of mTOR and MEK/ERK as a possible mechanism of resistance to CUDC-907.
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Affiliation(s)
- Shuang Liu
- Key Laboratory for Molecular Enzymology and Engineering, National Engineering Laboratory for AIDS Vaccine, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, China
| | - Shoujing Zhao
- Key Laboratory for Molecular Enzymology and Engineering, National Engineering Laboratory for AIDS Vaccine, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, China
| | - Yang Dong
- Key Laboratory for Molecular Enzymology and Engineering, National Engineering Laboratory for AIDS Vaccine, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, China
| | - Tingting Wang
- Key Laboratory for Molecular Enzymology and Engineering, National Engineering Laboratory for AIDS Vaccine, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, China
| | - Xiaojia Niu
- Key Laboratory for Molecular Enzymology and Engineering, National Engineering Laboratory for AIDS Vaccine, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, China
| | - Lijing Zhao
- Department of Rehabilitation, School of Nursing, Jilin University, Changchun, China
| | - Guan Wang
- Key Laboratory for Molecular Enzymology and Engineering, National Engineering Laboratory for AIDS Vaccine, The Ministry of Education, School of Life Sciences, Jilin University, 2699 Qianjin Street, Changchun, Jilin, China.
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27
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Knudsen ES, Kumarasamy V, Chung S, Ruiz A, Vail P, Tzetzo S, Wu J, Nambiar R, Seshadri M, Abrams SI, Wang J, Witkiewicz AK, Wang J, Witkiewicz AK. Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer. Gut 2021; 70:127-138. [PMID: 32424005 PMCID: PMC7671951 DOI: 10.1136/gutjnl-2020-321000] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/30/2020] [Accepted: 04/19/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVE This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer. DESIGN Patient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment. RESULTS We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. CONCLUSIONS Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.
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Affiliation(s)
- Erik s Knudsen
- Center for Personalized Medicine, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA,Molecular & Cellular Biology, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA
| | - Vishnu Kumarasamy
- Center for Personalized Medicine, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA,Molecular & Cellular Biology, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA
| | - Sejin Chung
- Center for Personalized Medicine, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA,Molecular & Cellular Biology, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA
| | - Amanda Ruiz
- Cancer Center, University of Arizona, Tucson, Arizona,
USA
| | - Paris Vail
- Center for Personalized Medicine, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA,Molecular & Cellular Biology, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA
| | - Stephanie Tzetzo
- Immunology, Roswell Park Comprehensive Cancer Center,
Buffalo, New York, USA
| | - Jin Wu
- Center for Personalized Medicine, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA
| | - Ram Nambiar
- Center for Personalized Medicine, Roswell Park
Comprehensive Cancer Center, Buffalo, New York, USA
| | - Mukund Seshadri
- Oral Oncology, Roswell Park Comprehensive Cancer Center,
Buffalo, New York, USA
| | - Scott I Abrams
- Immunology, Roswell Park Comprehensive Cancer Center,
Buffalo, New York, USA
| | - Jianmin Wang
- Biostatistics and Bioinformatics, Roswell Park
comprehensive Cancer Center, Buffalo, New York, USA
| | - Agnieszka K Witkiewicz
- Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA .,Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
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28
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Kumari N, Singh RK, Mishra SK, L R, Mohindra S, Krishnani N. Prevalence and spectrum of pathogenic germline variants in intestinal and pancreatobiliary type of ampullary cancer. Pathol Res Pract 2020; 217:153309. [PMID: 33341547 DOI: 10.1016/j.prp.2020.153309] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 11/20/2020] [Accepted: 12/01/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Ampullary cancer may occur as a component of hereditary cancer syndromes. Mutations in inherited cancer susceptibility genes play a therapeutic role and its knowledge in ampullary cancer is lacking. METHODS Thirty-seven cases of ampullary carcinoma were subjected to tumor-normal whole exome sequencing with mean coverage of 100X (blood) and 200X (tumor). Data were analyzed and correlated with intestinal and pancreatobiliary differentiation. RESULTS There were 22 intestinal, 13 pancreatobiliary and 2 cases of mixed differentiation. One hundred and forty-three germline variations with at least >1 pathogenic germline variants (PGVs) across 83 genes were found in 36 of 37 patients. Twelve genes (14.5 %) showed >3, 20 genes (24.1 %) showed two and 51 genes (61.4 %) showed one PGVs. Intestinal differentiation showed higher PGVs (117 variants, 73 genes) than pancreatobiliary differentiation (85 variants, 62 genes). PGVs in ERCC5, MEN1, MSH3, CHEK1, TP53, APC, FANCA, ERBB2, BRCA1, BRCA2, RTEL1, HNF1A and PTCH1 were seen in >50 % of cases. Nine genes harbored somatic second hits in 14 cases. PGVs in DNA damage-repair, homologous recombination repair, TP53 transcriptional regulation, DNA double stranded breaks, cell cycle and nucleotide excision repair genes were seen in all cases of intestinal and pancreatobiliary differentiation, while DNA mismatch repair genes were found in 81.8 % of intestinal and 84.6 % of pancreatobiliary cancers. Functional pathway analysis showed that DNA damage-repair, double stranded break repair, mismatch repair, homologous recombination repair and TP53 transcriptional regulation genes were altered in both while nucleotide-excision repair was significantly mutated in intestinal type and cell-cycle genes in pancreatobiliary type (p < 0.05). CONCLUSION This study reports spectrum of PGVs in intestinal and pancreatobiliary differentiation of ampullary carcinoma at higher frequency through whole exome sequencing. PGVs were most frequently found in DNA repair genes. Detecting PGVs through tumor-normal sequencing may identify therapeutically actionable and double-hit mutations that can guide towards appropriate management.
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Affiliation(s)
- Niraj Kumari
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
| | - Rajneesh K Singh
- Department of Surgical Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
| | - Shravan K Mishra
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
| | - Raghvendra L
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
| | - Samir Mohindra
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
| | - Narendra Krishnani
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
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Oshi M, Newman S, Tokumaru Y, Yan L, Matsuyama R, Endo I, Katz MHG, Takabe K. High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection. Cancers (Basel) 2020; 12:E2871. [PMID: 33036243 PMCID: PMC7599494 DOI: 10.3390/cancers12102871] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 12/21/2022] Open
Abstract
Pancreatic cancer is highly mortal due to uncontrolled cell proliferation. The G2M checkpoint pathway is an essential part of the cell cycle. We hypothesized that a high G2M pathway score is associated with cell proliferation and worse survival in pancreatic cancer patients. Gene set variation analysis using the Hallmark G2M checkpoint gene set was used as a score to analyze a total of 390 human pancreatic cancer patients from 3 cohorts (TCGA, GSE62452, GSE57495). High G2M score tumors enriched other cell proliferation genes sets as well as MKI67 expression, pathological grade, and proliferation score. Independent of other prognostic factors, G2M score was predictive of disease-specific survival in pancreatic cancer. High G2M tumor was associated with high mutation rate of KRAS and TP53 and significantly enriched these pathway gene sets, as well as high infiltration of Th2 cells. High G2M score consistently associated with worse overall survival in 3 cohorts, particularly in R1/2 resection, but not in R0. High G2M tumor in R1/2 highly enriched metabolic and cellular components' gene sets compared to R0. To our knowledge, this is the first study to use gene set variation analysis as a score to examine the clinical relevancy of the G2M pathway in pancreatic cancer.
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Affiliation(s)
- Masanori Oshi
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.O.); (R.M.); (I.E.)
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.); (Y.T.)
| | - Stephanie Newman
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.); (Y.T.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.); (Y.T.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.O.); (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.O.); (R.M.); (I.E.)
| | - Matthew H. G. Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Kazuaki Takabe
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.O.); (R.M.); (I.E.)
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.); (Y.T.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
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30
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Qian Y, Gong Y, Fan Z, Luo G, Huang Q, Deng S, Cheng H, Jin K, Ni Q, Yu X, Liu C. Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma. J Hematol Oncol 2020; 13:130. [PMID: 33008426 PMCID: PMC7532113 DOI: 10.1186/s13045-020-00958-3] [Citation(s) in RCA: 192] [Impact Index Per Article: 38.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 08/31/2020] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.
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Affiliation(s)
- Yunzhen Qian
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Yitao Gong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Zhiyao Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
| | - Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Qiuyi Huang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Shengming Deng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - He Cheng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, NO.270 DongAn Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
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31
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Shams R, Asadzadeh Aghdaei H, Behmanesh A, Sadeghi A, Zali M, Salari S, Padrón JM. MicroRNAs Targeting MYC Expression: Trace of Hope for Pancreatic Cancer Therapy. A Systematic Review. Cancer Manag Res 2020; 12:2393-2404. [PMID: 32308478 PMCID: PMC7132265 DOI: 10.2147/cmar.s245872] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/13/2020] [Indexed: 12/12/2022] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and a major health problem worldwide. There were no major advances in conventional treatments in inhibiting tumor progression and increasing patient survival time. In order to suppress mechanisms responsible for tumor cell development such as those with oncogenic roles, more advanced therapeutic strategies should be sought. One of the most important oncogenes of pancreatic cancer is the MYC gene. The overexpression of MYC can activate many tumorigenic processes such as cell proliferation and pancreatic cancer cell invasion. MiRNAs are important molecules that are confirmed by targeting mRNA transcripts to regulate the expression of the MYC gene. Therefore, restoring MYC-repressing miRNAs expression tends to be an effective method of treating MYC-driven cancers. Objective The purpose of this study was to identify all validated microRNAs targeting C-MYC expression to inhibit PDAC progression by conducting a systematic review. Methods In this systematic review study, the papers published between 2000 and 2020 in major online scientific databases including PubMed, Scopus, and Web of Science were screened, following inclusion and exclusion criteria. We extracted all the experimental studies that showed miRNAs could target the expression of the MYC gene in PDAC. Results Eight papers were selected from a total of 89 papers. We found that six miRNAs (Let-7a, miR-145, miR-34a, miR-375, miR-494, and miR-148a) among the selected studies were validated for targeting MYC gene and three of them confirmed Let-7a as a direct MYC expression regulator in PC cells. Finally, we summarized the latest shreds of evidence of experimentally validated miRNAs targeting the MYC gene with respect to PDAC’s therapeutic potential. Conclusion Restoring the expression of MYC-repressing miRNAs tends to be an effective way to treat MYC-driven cancers such as PDAC. Several miRNAs have been proposed to target this oncogene via bioinformatics tools, but only a few have been experimentally validated for pancreatic cancer cells and models. Further studies should be conducted to find the interaction network of miRNA-MYC to develop more successful therapeutic strategies for PC, using the synergistic effects of these miRNAs.
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Affiliation(s)
- Roshanak Shams
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Behmanesh
- Student Research Committee, School of Health Management and Information Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Sadeghi
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadareza Zali
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Salari
- Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - José M Padrón
- BioLab, Instituto Universitario de Bio-Orgánica "Antonio González" (IUBO-AG), Universidad de la Laguna, La Laguna, Spain
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32
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Oncolytic Virus-Mediated Targeting of the ERK Signaling Pathway Inhibits Invasive Propensity in Human Pancreatic Cancer. MOLECULAR THERAPY-ONCOLYTICS 2020; 17:107-117. [PMID: 32322667 PMCID: PMC7163052 DOI: 10.1016/j.omto.2020.03.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 03/25/2020] [Indexed: 12/19/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) cells have an exceptional ability to invade nerves through pronounced crosstalk between nerves and cancer cells; however, the mechanism of PDAC cell invasion remains to be elucidated. Here, we demonstrate the therapeutic potential of telomerase-specific oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, against human PDAC cells. Highly invasive PDAC cells exhibited higher levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) expression independent of KRAS expression; ERK1/2 inhibitor or small interfering RNA (siRNA) treatment significantly reduced the migration and invasion of PDAC cells, suggesting that the ERK signaling pathway is associated with the invasiveness of PDAC cells. OBP-702 infection suppressed ERK signaling and inhibited PDAC cell migration and invasion more efficiently than OBP-301. OBP-702 also effectively inhibited PDAC cell invasion even when invasiveness was enhanced by administration of motility stimulators, such as nerve and neurosecretory factors. Moreover, noninvasive whole-body imaging analyses showed that OBP-702 significantly suppressed tumor growth in an orthotopic PDAC xenograft model, although both viruses were equally effective against subcutaneous tumors, suggesting that OBP-702 can influence the orthotopic tumor microenvironment. Our data suggest that oncolytic virus-mediated disruption of ERK signaling is a promising antitumor strategy for attenuating the invasiveness of PDAC cells.
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33
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Wu C, Yang P, Liu B, Tang Y. Is there a CDKN2A-centric network in pancreatic ductal adenocarcinoma? Onco Targets Ther 2020; 13:2551-2562. [PMID: 32273725 PMCID: PMC7108878 DOI: 10.2147/ott.s232464] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 02/19/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer has a high mortality rate and its incidence has risen rapidly in recent years. Meanwhile, the diagnosis and treatment of this cancer remain challenging. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, but, currently, no sufficiently effective modalities for its treatment exist. The early diagnosis rate of pancreatic cancer is low and most patients have reached an advanced stage at the time of diagnosis. PDAC evolves from precancerous lesions and is highly aggressive and metastatic. It is essential to understand how the disease progresses and metastasizes. CDKN2A mutations are very common in PDAC. Therefore, here, we have performed a literature review and discuss the role of CDKN2A and some related genes in the development of PDAC, as well as the basis of gene targeting with a correlation coefficient of CDKN2A above 0.9 on the STRING website. It is noteworthy that the interaction of CDKN2A with each gene has been reported in the literature. The role of these genes and CDKN2A in PDAC may provide new directions that will advance the current knowledge base and treatment options since cancer progression is realized through interactions among cells. Our findings provide new insights into the treatment of PADC that can, to some extent, improve the diagnosis rate and quality of life of patients.
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Affiliation(s)
- Chu Wu
- Cancer Research Institute, Key Laboratory of Tumor Cellular & Molecular Pathology, Medical College of Hengyang, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Ping Yang
- Cancer Research Institute, Key Laboratory of Tumor Cellular & Molecular Pathology, Medical College of Hengyang, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Bingxue Liu
- Cancer Research Institute, Key Laboratory of Tumor Cellular & Molecular Pathology, Medical College of Hengyang, University of South China, Hengyang, Hunan 421001, People's Republic of China
| | - Yunlian Tang
- Cancer Research Institute, Key Laboratory of Tumor Cellular & Molecular Pathology, Medical College of Hengyang, University of South China, Hengyang, Hunan 421001, People's Republic of China
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Oliverius M, Flasarova D, Mohelnikova-Duchonova B, Ehrlichova M, Hlavac V, Kocik M, Strouhal O, Dvorak P, Ojima I, Soucek P. KRAS pathway expression changes in pancreatic cancer models by conventional and experimental taxanes. Mutagenesis 2019; 34:403-411. [PMID: 31375828 PMCID: PMC6923165 DOI: 10.1093/mutage/gez021] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 07/06/2019] [Indexed: 12/30/2022] Open
Abstract
The KRAS signalling pathway is pivotal for pancreatic ductal adenocarcinoma (PDAC) development. After the failure of most conventional cytotoxic and targeted therapeutics tested so far, the combination of taxane nab-paclitaxel (Abraxane) with gemcitabine recently demonstrated promising improvements in the survival of PDAC patients. This study aimed to explore interactions of conventional paclitaxel and experimental taxane SB-T-1216 with the KRAS signalling pathway expression in in vivo and in vitro PDAC models in order to decipher potential predictive biomarkers or targets for future individualised therapy. Mouse PDAC PaCa-44 xenograft model was used for evaluation of changes in transcript and protein levels of the KRAS signalling pathway caused by administration of experimental taxane SB-T-1216 in vivo. Subsequently, KRAS wild-type (BxPc-3) and mutated (MiaPaCa-2 and PaCa-44) cell line models were treated with paclitaxel to verify dysregulation of the KRAS signalling pathway gene expression profile in vitro and investigate the role of KRAS mutation status. By comparing the gene expression profiles, this study observed for the first time that in vitro cell models differ in the basal transcriptional profile of the KRAS signalling pathway, but there were no differences between KRAS mutated and wild-type cells in sensitivity to taxanes. Generally, the taxane administration caused a downregulation of the KRAS signalling pathway both in vitro and in vivo, but this effect was not dependent on the KRAS mutation status. In conclusion, putative biomarkers for prediction of taxane activity or targets for stimulation of taxane anticancer effects were not discovered by the KRAS signalling pathway profiling in various PDAC models.
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Affiliation(s)
- M Oliverius
- Department of Surgery, Faculty Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic
- Transplantation Center, Institute of Clinical and Experimental Medicine, Prague, Czech Republic
| | - D Flasarova
- Department of Oncology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - B Mohelnikova-Duchonova
- Department of Oncology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
- Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic
| | - M Ehrlichova
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - V Hlavac
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - M Kocik
- Transplantation Center, Institute of Clinical and Experimental Medicine, Prague, Czech Republic
| | - O Strouhal
- Department of Oncology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - P Dvorak
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - I Ojima
- Institute of Chemical Biology and Drug Discovery, State University of New York at Stony Brook, Stony Brook, NY, USA
| | - P Soucek
- Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
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Palacio S, McMurry HS, Ali R, Donenberg T, Silva-Smith R, Wideroff G, Sussman DA, Rocha Lima CMS, Hosein PJ. DNA damage repair deficiency as a predictive biomarker for FOLFIRINOX efficacy in metastatic pancreatic cancer. J Gastrointest Oncol 2019; 10:1133-1139. [PMID: 31949930 DOI: 10.21037/jgo.2019.09.12] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Patients with pathogenic germline and somatic variants in DNA damage repair (DDR) genes may derive greater benefit with platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC). This study investigates the role of DDR genes as a predictive biomarker for response to first-line platinum chemotherapy with FOLFIRINOX in metastatic PDAC patients. Demographic, clinical, and pathologic variables were collected for patients with metastatic PDAC who received FOLFIRINOX as frontline treatment and who had germline and somatic genetic testing. Kaplan-Meier analysis of overall survival (OS) and progression free survival (PFS) were correlated to the presence of DDR pathogenic variants. Forty patients with metastatic PDAC met inclusion criteria. Germline genetic testing revealed germline pathogenic variants in DDR genes in 5 patients (12%), and somatic pathogenic variants in DDR genes in 4 patients (10%). Median PFS was significantly longer in patients with any (germline or somatic) pathogenic variant in DDR genes than in those without alterations 18.5 vs. 6.9 months (log-rank P=0.003). When restricted to the presence or absence of germline pathogenic variants in DDR genes, the median PFS was 18.5 vs. 7.4 months (log-rank P=0.005). The median OS for the entire cohort was 11.5 months was not statistically different between the two groups, however there were no deaths in the subgroup with germline pathogenic variants in DDR genes treated with frontline FOLFIRINOX. A subset of patients with metastatic PDAC and germline or somatic pathogenic variants in DDR genes have a statistically superior PFS when treated with the platinum containing regimen FOLFIRINOX. The role of DDR gene alterations as a predictive biomarker for FOLFIRINOX benefit should be further evaluated in prospective trials.
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Affiliation(s)
- Sofia Palacio
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Hannah S McMurry
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Robert Ali
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Talia Donenberg
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Rachel Silva-Smith
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Gina Wideroff
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | - Daniel A Sussman
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
| | | | - Peter J Hosein
- Department of Medicine, University of Miami Miller School of Medicine, and Sylvester Comprehensive Cancer Center, Miami, FL, USA
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Jin F, Xiao D, Zhao T, Yu M. Proteasome inhibitor MG132 suppresses pancreatic ductal adenocarcinoma-cell migration by increasing ESE3 expression. Oncol Lett 2019; 19:858-868. [PMID: 31897200 PMCID: PMC6924158 DOI: 10.3892/ol.2019.11157] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 09/27/2019] [Indexed: 12/26/2022] Open
Abstract
The clinical significance of the proteasome inhibitor MG132 has been examined in numerous human cancer types; however, its influence on the metastasis and progression of pancreatic cancer is yet to be determined. In the present study, the effect of MG132 treatment on pancreatic ductal adenocarcinoma (PDAC) cell lines (SW1990 and PANC-1) was examined. Compared with the control groups, MG132 treatment resulted in higher expression levels of ETS homologous factor (ESE3), a crucial member of the E26 transformation-specific family that is central to various differentiation and development processes in epithelial tissues. MG132 treatment also increased the nuclear translocation of ESE3. Mechanistically, MG132 further inhibited the invasion and migration of PDAC cells by promoting E-cadherin expression, which not only plays an important role in cell-cell adhesion, but is also a direct target of ESE3. Furthermore, subsequent knockdown experiments, using short interfering RNAs, demonstrated that MG132 upregulated E-cadherin via an increase in ESE3 expression. The results of the present study support the hypothesis that MG132 treatment inhibits PDAC metastasis, highlighting the potential of MG132 as a therapeutic agent for the treatment of patients with PDAC.
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Affiliation(s)
- Fanjie Jin
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China
| | - Di Xiao
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Tiansuo Zhao
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China
| | - Ming Yu
- Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, P.R. China
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Kumarasamy V, Ruiz A, Nambiar R, Witkiewicz AK, Knudsen ES. Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer. Oncogene 2019; 39:1831-1845. [PMID: 31745297 PMCID: PMC7047578 DOI: 10.1038/s41388-019-1102-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 10/26/2019] [Accepted: 11/05/2019] [Indexed: 12/22/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease characterized by the aberrations in multiple genes that drive pathogenesis and limit therapeutic response. While CDK4/6 represents a downstream target of both KRAS mutation and loss of the CDKN2A tumor suppressor in PDAC, clinical and preclinical studies indicate that pharmacological CDK4/6 inhibitors are only modestly effective. Since chemotherapy represents the established backbone of PDAC treatment we evaluated the interaction of CDK4/6 inhibitors with gemcitabine and taxanes that are employed in the treatment of PDAC. Herein, we demonstrate that the difference in mechanisms of actions of chemotherapeutic agents elicit distinct effects on the cellular response to CDK4/6 inhibition. Gemcitabine largely ablates the function of CDK4/6 inhibition in S-phase arrested cells when administered contemporaneously; although, when cells recover from S-phase block they exhibit sensitivity to CDK4/6 inhibition. In contrast, pharmacological inhibition of CDK4/6 yields a cooperative cytostatic effect in combination with docetaxel and prevents adaptation and cell cycle re-entry, which is a common basis for resistance to such agents. Importantly, using organoid and PDX models we could confirm the cooperative effects between chemotherapy and CDK4/6 inhibition. These data indicate that the combination of cytotoxic and cytostatic agents could represent an important modality in those tumor types that are relatively resistant to CDK4/6 inhibitors.
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Affiliation(s)
- Vishnu Kumarasamy
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Amanda Ruiz
- Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Ram Nambiar
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Agnieszka K Witkiewicz
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. .,Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
| | - Erik S Knudsen
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. .,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
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38
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Ren S, Zhang J, Chen J, Cui W, Zhao R, Qiu W, Duan S, Chen R, Chen X, Wang Z. Evaluation of Texture Analysis for the Differential Diagnosis of Mass-Forming Pancreatitis From Pancreatic Ductal Adenocarcinoma on Contrast-Enhanced CT Images. Front Oncol 2019; 9:1171. [PMID: 31750254 PMCID: PMC6848378 DOI: 10.3389/fonc.2019.01171] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/18/2019] [Indexed: 12/13/2022] Open
Abstract
Purpose: To investigate the potential of computed tomography (CT) imaging features and texture analysis to differentiate between mass-forming pancreatitis (MFP) and pancreatic ductal adenocarcinoma (PDAC). Materials and Methods: Thirty patients with pathologically proved MFP and 79 patients with PDAC were included in this study. Clinical data and CT imaging features of the two lesions were evaluated. Texture features were extracted from arterial and portal phase CT images using commercially available software (AnalysisKit). Multivariate logistic regression analyses were used to identify relevant CT imaging and texture parameters to discriminate MFP from PDAC. Receiver operating characteristic curves were performed to determine the diagnostic performance of predictions. Results: MFP showed a larger size compared to PDAC (p = 0.009). Cystic degeneration, pancreatic ductal dilatation, vascular invasion, and pancreatic sinistral portal hypertension were more frequent and duct penetrating sign was less frequent in PDAC compared to MFP. Arterial CT attenuation, arterial, and portal enhancement ratios of MFP were higher than PDAC (p < 0.05). In multivariate analysis, arterial CT attenuation and pancreatic duct penetrating sign were independent predictors. Texture features in arterial phase including SurfaceArea, Percentile40, InverseDifferenceMoment_angle90_offset4, LongRunEmphasis_angle45_offset4, and uniformity were independent predictors. Texture features in portal phase including LongRunEmphasis_angle135_offset7, VoxelValueSum, LongRunEmphasis_angle135_offset4, and GLCMEntropy_angle45_offset1 were independent predictors. Areas under the curve of imaging feature-based, texture feature-based in arterial and portal phases, and the combined models were 0.84, 0.96, 0.93, and 0.98, respectively. Conclusions: CT texture analysis demonstrates great potential to differentiate MFP from PDAC.
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Affiliation(s)
- Shuai Ren
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Jingjing Zhang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Jingya Chen
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Wenjing Cui
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Rui Zhao
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Wenli Qiu
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | | | - Rong Chen
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Xiao Chen
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Zhongqiu Wang
- Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
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39
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Fong CYK, Burke E, Cunningham D, Starling N. Up-to-Date Tailored Systemic Treatment in Pancreatic Ductal Adenocarcinoma. Gastroenterol Res Pract 2019; 2019:7135437. [PMID: 31582971 PMCID: PMC6748185 DOI: 10.1155/2019/7135437] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/09/2019] [Indexed: 12/24/2022] Open
Abstract
Despite intensive research efforts, pancreatic ductal adenocarcinoma is still regarded as an aggressive and life-limiting malignancy. Combination chemotherapy regimens that underpin the current treatment approach in the advanced setting have led to incremental survival gains in recent years but have failed to confer patients with a median overall survival that exceeds 12 months from diagnosis. Research has since focussed on understanding the role and interplay between various components of the desmoplastic stroma and tumour microenvironment, in addition to developing targeted therapies based on molecular features to improve the prognosis associated with this malignancy. This review will summarise the available systemic treatment options and discuss potential methods to refine the resolution of patient selection to enhance responses to currently available therapies. Furthermore, it will explore newer approaches anticipated to come to the fore of future clinical practice, such as agents targeting the DNA damage response and tumour microenvironment as well as immunotherapy-based combinations.
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Affiliation(s)
| | - Emma Burke
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
| | - David Cunningham
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
| | - Naureen Starling
- The Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, UK
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40
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Martens S, Lefesvre P, Nicolle R, Biankin AV, Puleo F, Van Laethem JL, Rooman I. Different shades of pancreatic ductal adenocarcinoma, different paths towards precision therapeutic applications. Ann Oncol 2019; 30:1428-1436. [PMID: 31161208 DOI: 10.1093/annonc/mdz181] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/09/2023] Open
Abstract
BACKGROUND Different histological and molecular subtypes of pancreatic ductal adenocarcinoma (PDAC), with different molecular composition and survival statistics, have recently been recognised. MATERIALS AND METHODS This review describes the currently available studies regarding molecular and histological subtypes in PDAC. Studies from major cohorts such as International Cancer Genome Consortium as well as smaller cohorts are reviewed. We discuss where the described subtypes overlap, where the discrepancies are and which paths forward could be taken regarding diagnosis, ontogeny and therapy. RESULTS Four molecular subtypes with strong overlap among the different studies can be found, next to a list of mixed findings. Two of the four subtypes (epithelial classical and mesenchymal basal-like) were represented in every study and were often discriminated in other solid tumours as well. These two subtypes differ substantially in prognosis. One biomarker has been discovered, only discriminating these two subtypes, and insights into subtype-specific therapeutic vulnerabilities are scarce. CONCLUSION Subtypes can be reproducibly detected in cohorts of PDAC patients and two of them directly relate with prognosis. A consensus on the subtypes is warranted. Further discovery and validation studies are needed to identify strong biomarkers, to comprehend subtype ontogeny and to define strategies for precision medicine.
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Affiliation(s)
- S Martens
- Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Brussels
| | - P Lefesvre
- Department of Pathology, UZ Brussel, Brussels, Belgium
| | - R Nicolle
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France
| | - A V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - F Puleo
- Medical Oncology Department, Institut Jules Bordet; Laboratory of Experimental Gastroenterology
| | - J L Van Laethem
- Laboratory of Experimental Gastroenterology; Department of Gastroenterology and Digestive Oncology, Hospital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
| | - I Rooman
- Laboratory of Medical and Molecular Oncology, Vrije Universiteit Brussel, Brussels.
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41
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MCOLN1 Promotes Proliferation and Predicts Poor Survival of Patients with Pancreatic Ductal Adenocarcinoma. DISEASE MARKERS 2019; 2019:9436047. [PMID: 31481985 PMCID: PMC6701426 DOI: 10.1155/2019/9436047] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 06/10/2019] [Accepted: 07/16/2019] [Indexed: 12/15/2022]
Abstract
Background MCOLN1 (mucolipin subfamily, member 1) was first identified as an autophagic regulator, which was essential for efficient fusion of both autophagosomes and late endosomes with lysosomes. This study is aimed at investigating the role of MCOLN1 in the development of pancreatic ductal adenocarcinoma (PDAC). Methods Immunohistochemistry (IHC) assay was conducted to evaluate the expression level of MCOLN1 in 82 human PDAC tumor tissues. Overall survival (OS) and recurrence-free survival (RFS) analysis was performed to assess the prognosis of patients. Colony formation and MTT assays [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] were performed to measure the proliferation capacity of tumor cells. The expression level of related genes was measured by RT-PCR (reverse transcription polymerase chain reaction) and western blot assays. The animal model was used to examine the effects of indicated protein on tumorigenesis in vivo. Results The results of IHC showed that a high level of MCOLN1 expression was associated with the poor clinical characteristics of PDAC patients. OS and RFS were significantly worse in patients with high MCOLN1 expression. Silencing of MCOLN1 dramatically blocked the proliferation of PDAC cells. Mechanism studies confirmed that knockdown of MCOLN1 decreased the expression of Ki67 and PCNA (proliferating cell nuclear antigen), two markers of cell proliferation. In vivo, MCOILN1 depletion reduced the formation and growth of tumors in mice. Conclusion The high level of MCOLN1 expression was associated with poor clinical outcomes of PDAC patients. MCOLN1 ablation could inhibit PDAC proliferation of both in vitro and in vivo, which provide a new insight and novel therapeutic target for the treatment of PDAC.
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42
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Hung YH, Hsu MC, Chen LT, Hung WC, Pan MR. Alteration of Epigenetic Modifiers in Pancreatic Cancer and Its Clinical Implication. J Clin Med 2019; 8:jcm8060903. [PMID: 31238554 PMCID: PMC6617267 DOI: 10.3390/jcm8060903] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/15/2019] [Accepted: 06/20/2019] [Indexed: 12/12/2022] Open
Abstract
The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms for early detection. Approximately 55% of all patients are diagnosed with pancreatic cancer only after the tumors metastasize. Therefore, identifying useful biomarkers for early diagnosis and screening high-risk groups are important to improve pancreatic cancer therapy. Recent emerging evidence has suggested that genetic and epigenetic alterations play a crucial role in the molecular aspects of pancreatic tumorigenesis. Here, we summarize recent progress in our understanding of the epigenetic alterations in pancreatic cancer and propose potential synthetic lethal strategies to target these genetic defects to treat this deadly disease.
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Affiliation(s)
- Yu-Hsuan Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
| | - Ming-Chuan Hsu
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Mei-Ren Pan
- Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
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43
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Cloyd JM, Katz MHG, Wang H, Cuddy A, You YN. Clinical and Genetic Implications of DNA Mismatch Repair Deficiency in Patients With Pancreatic Ductal Adenocarcinoma. JAMA Surg 2019; 152:1086-1088. [PMID: 28793134 DOI: 10.1001/jamasurg.2017.2631] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Jordan M Cloyd
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Matthew H G Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Huamin Wang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston
| | - Amanda Cuddy
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston
| | - Y Nancy You
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston
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44
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Wood LD, Yurgelun MB, Goggins MG. Genetics of Familial and Sporadic Pancreatic Cancer. Gastroenterology 2019; 156:2041-2055. [PMID: 30660730 DOI: 10.1053/j.gastro.2018.12.039] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 11/14/2018] [Accepted: 12/05/2018] [Indexed: 12/14/2022]
Abstract
In the previous decade, comprehensive genomic analyses have yielded important insights about the genetic alterations that underlie pancreatic tumorigenesis. Whole-exome and whole-genome sequencing of pancreatic ductal adenocarcinomas have confirmed the critical driver genes altered in the majority of pancreatic cancers, as well as identified numerous less frequently altered driver genes, and have delineated cancer subgroups with unique biological and clinical features. It is now appreciated that pancreatic susceptibility gene alterations are often identified in patients with pancreatic cancer without family histories suggestive of a familial cancer syndrome, prompting recent efforts to expand gene testing to all patients with pancreatic cancer. Studies of pancreatic cancer precursor lesions have begun to elucidate the evolutionary history of pancreatic tumorigenesis and to help us understand the utility of biomarkers for early detection and targets to develop new therapeutic strategies. In this review, we discuss the results of comprehensive genomic characterization of pancreatic ductal adenocarcinoma and its precursor lesions, and we highlight translational applications in early detection and therapy.
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Affiliation(s)
- Laura D Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| | - Matthew B Yurgelun
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
| | - Michael G Goggins
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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45
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Liu X, Luo X, Jiang C, Zhao H. Difficulties and challenges in the development of precision medicine. Clin Genet 2019; 95:569-574. [PMID: 30653655 DOI: 10.1111/cge.13511] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 01/09/2019] [Accepted: 01/11/2019] [Indexed: 12/25/2022]
Abstract
The rapid development of precision medicine is introducing a new era of significance in medicine. However, attaining precision medicine is an ambitious goal that is bound to encounter some challenges. Here, we have put forward some difficulties or questions that should be addressed by the progress in this field. The proposed issues include the long road to precision medicine for all types of diseases as the unknown domains of the human genome hinder the development of precision medicine. The challenges in the acquisition and analysis of large amounts of omics data, including difficulties in the establishment of a library of biological samples and large-scale data analysis, as well as the challenges of informed consent and medical ethics in precision medicine, must be overcome to attain the goals of precision medicine. To date, precision medicine programs have accomplished many preliminary achievements and will help to drive a dramatic revolution in clinical practices for the medical community. Through these advances, the diagnosis and treatment of many diseases will achieve many breakthroughs. This project is just beginning and requires a great deal of time and money. Precision medicine also requires extensive collaboration. Ultimately, these difficulties can be overcome. We should realize that precision medicine is good for patients, but there is still a long way to go.
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Affiliation(s)
- Xiaoqin Liu
- Department of Nephrology, Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, People's Republic of China
| | - Xin Luo
- Department of Radiotherapy, The Second Hospital of PingLiang City, Second Affiliated Hospital of Gansu Medical College, Pingliang, People's Republic of China
| | - Chunyang Jiang
- Department of Thoracic Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
| | - Hui Zhao
- Department of Thoracic Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
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46
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Knudsen ES, Kumarasamy V, Ruiz A, Sivinski J, Chung S, Grant A, Vail P, Chauhan SS, Jie T, Riall TS, Witkiewicz AK. Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer. Oncogene 2019; 38:3355-3370. [PMID: 30696953 PMCID: PMC6499706 DOI: 10.1038/s41388-018-0650-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 11/18/2018] [Accepted: 11/19/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A that encodes an endogenous CDK4/6 inhibitor to bypass the RB-mediated cell cycle suppression. Analysis of a panel of patient-derived cell lines and matched xenografts indicated that many pancreatic cancers have intrinsic resistance to CDK4/6 inhibition that is not due to any established mechanism or published biomarker. Rather, there is a KRAS-dependent rapid adaptive response that leads to the upregulation of cyclin proteins, which participate in functional complexes to mediate resistance. In vivo, the degree of response is associated with the suppression of a gene-expression signature that is strongly prognostic in pancreatic cancer. Resistance is associated with an adaptive gene expression signature which is common to multiple kinase inhibitors, but is attenuated with MTOR inhibitors. Combination treatment with MTOR and CDK4/6 inhibitors had potent activity across a large number of patient derived models of PDAC underscoring the potential clinical efficacy.
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Affiliation(s)
- Erik S Knudsen
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. .,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA.
| | - Vishnu Kumarasamy
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Amanda Ruiz
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Jared Sivinski
- Department of Pharmacology, Universtiy of Arizona, Tucson, AZ, USA
| | - Sejin Chung
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Adam Grant
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Paris Vail
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY, USA
| | | | - Tun Jie
- Department of Surgery, University of Arizona, Tucson, AZ, USA
| | - Taylor S Riall
- Department of Surgery, University of Arizona, Tucson, AZ, USA
| | - Agnieszka K Witkiewicz
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA. .,Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA.
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47
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Wong W, Lowery MA, Berger MF, Kemel Y, Taylor B, Zehir A, Srinivasan P, Bandlamudi C, Chou J, Capanu M, Varghese A, Yu KH, Iacobuzio-Donahue CA, Shia J, Klimstra DS, Jarnagin WR, Stadler ZK, O'Reilly EM. Ampullary cancer: Evaluation of somatic and germline genetic alterations and association with clinical outcomes. Cancer 2019; 125:1441-1448. [PMID: 30620386 DOI: 10.1002/cncr.31951] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 10/27/2018] [Accepted: 10/31/2018] [Indexed: 12/19/2022]
Abstract
BACKGROUND Ampullary carcinoma (AC) is a rare gastrointestinal cancer. Pathogenic germline alterations (PGAs) in BRCA2 and potentially targetable somatic alterations (SAs) in ERBB2 and ELF3 have been previously described in AC. Memorial Sloan Kettering Cancer Center has implemented an opt-in strategy for germline testing (GT) and somatic testing (ST) for patients with AC to further evaluate the spectrum of PGAs and SAs. METHODS Forty-five patients with pathologically confirmed AC prospectively consented with the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) test (410-468 genes). A subset of the cohort (23 of the 45 patients) also consented to GT with MSK-IMPACT (76-88 genes). Germline data for 21 of the remaining 22 patients who had not consented to GT were obtained in a de-identified fashion without clinical correlation. Clinicopathologic features, treatment histories, and survival data for consenting patients were collected and analyzed. RESULTS Pancreaticobiliary, intestinal, and mixed features of the 2 types were the primary pathologic subtypes of AC identified in this cohort. No difference in median overall survival was found between pathologic subtypes. Eight of 44 patients (18%) were identified as harboring pathogenic mutations in BRCA2, ATM, RAD50, and MUTYH. In addition, this study found a wide spectrum of SAs in genes such as KRAS, MDM2, ERBB2, ELF3, and PIK3CA. Two patients in the cohort underwent SA-targeted therapy, and 1 had a partial radiographic response. CONCLUSIONS Mutations in multiple somatic and germline genes were identified in this cohort. Significantly, actionable targets were identified in the tumors, and broader testing for PGAs and SAs should be considered for all patients with AC.
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Affiliation(s)
- Winston Wong
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Maeve A Lowery
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, New York.,David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael F Berger
- Robert and Kate Niehaus Center for Inherited Genomics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yelena Kemel
- Robert and Kate Niehaus Center for Inherited Genomics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Barry Taylor
- Robert and Kate Niehaus Center for Inherited Genomics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ahmet Zehir
- Robert and Kate Niehaus Center for Inherited Genomics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Preethi Srinivasan
- Robert and Kate Niehaus Center for Inherited Genomics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chaitanya Bandlamudi
- Department of Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joanne Chou
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marinela Capanu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anna Varghese
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, New York.,David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kenneth H Yu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, New York.,David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Christine A Iacobuzio-Donahue
- David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David S Klimstra
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, New York.,David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, New York.,David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, New York
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48
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Chung S, Vail P, Witkiewicz AK, Knudsen ES. Coordinately Targeting Cell-Cycle Checkpoint Functions in Integrated Models of Pancreatic Cancer. Clin Cancer Res 2018; 25:2290-2304. [PMID: 30538111 DOI: 10.1158/1078-0432.ccr-18-1620] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 10/19/2018] [Accepted: 12/07/2018] [Indexed: 01/02/2023]
Abstract
PURPOSE Cancer cells often have deficiencies in cell-cycle control mechanisms and could be dependent on specific cell-cycle checkpoints to maintain viability. Because of the documented role of KRAS in driving replication stress, we targeted the checkpoint governing DNA replication using CHK1 kinase inhibitors in pancreatic ductal adenocarcinoma (PDAC) models and examined mechanisms of resistance. EXPERIMENTAL DESIGN Single-agent efficacy of CHK1 inhibition was investigated in established and primary PDAC lines. Drug screening was performed to identify cooperative agents. In vitro and in vivo studies were employed to interrogate combination treatment efficacy and mechanisms of resistance. RESULTS Many PDAC models evade single-agent inhibition through mechanisms that allow S-phase progression with CHK1 inhibited. Gene expression analysis revealed FOXM1 as a potential marker of CHK1 sensitivity and defined a form of pancreatic cancer with poor prognosis. Drug screen analysis identified WEE1 as a cooperative agent with CHK1 and was effective in cell culture. In vivo experiments validated the combination efficacy; however, resistance could evolve. Resistance was due to selection of a stable subclone from the original PDX tumor, which harbored high baseline replication stress. In vitro analysis revealed that gemcitabine could eliminate viability in the resistant models. The triplet regimen of gemcitabine, CHK1, and WEE1 inhibition provided strong disease control in all xenograft models interrogated. CONCLUSIONS These results demonstrate the therapeutic resiliency of pancreatic cancer and indicate that coordinately targeting cell-cycle checkpoints in concert with chemotherapy could be particularly efficacious.
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Affiliation(s)
- Sejin Chung
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York.,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York
| | - Paris Vail
- The University of Arizona Cancer Center, Tucson, Arizona
| | - Agnieszka K Witkiewicz
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York. .,Department of Pathology, Roswell Park Cancer Institute, Buffalo, New York
| | - Erik S Knudsen
- Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, New York. .,Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York
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49
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Ye J, Wen J, Ning Y, Li Y. Higher notch expression implies poor survival in pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. Pancreatology 2018; 18:954-961. [PMID: 30297095 DOI: 10.1016/j.pan.2018.09.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 09/26/2018] [Accepted: 09/28/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND At present, pancreatic ductal adenocarcinoma (PDAC) is a fetal disease lack of effective prognostic and therapeutic methods resulting in high mortality. The Notch signaling has been demonstrated being up- or down-regulated in many cancers, but the effects in pancreatic ductal adenocarcinoma are still controversial. Moreover, the available cases in an individual study are of small samples. Therefore, it is essential to define the effect of Notch signaling in pancreatic ductal adenocarcinoma with larger samples. METHODS Conducted from 6 eligible studies and 463 pancreatic ductal adenocarcinoma patients, this was the first meta-analysis to analyze the correlation between the Notch signal pathway and pancreatic ductal adenocarcinoma. All data were sourced from The National Center for Biotechnology Information, Web of Science and Cochrane. The articles which matched the inclusion criteria were included. All included data were analyzed and performed by Review Manager 5.3. RESULTS The results indicated that high expression of Notch signaling proteins was associated with poor overall survival of pancreatic ductal adenocarcinoma patients (pooled hazard ratio>2.00; P < 0.001). Moreover, poor survival was related to high expression of Notch3 (pooled hazard ratio: 2.05; confidence interval: 1.49-2.82; P < 0.001) and DLL4 (pooled hazard ratio: 2.13; confidence interval: 1.37-3.32; P < 0.001). CONCLUSIONS This meta-analysis supports that Notch signaling proteins may be available as prognostic factors for pancreatic ductal adenocarcinoma progression and patient survival. Higher expression of Notch signaling proteins indicated poor survival of pancreatic ductal adenocarcinoma patients. Targeting Notch signaling components, especially Notch3 protein, would be beneficial for therapies.
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Affiliation(s)
- Jianbin Ye
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Junjie Wen
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China
| | - Yunshan Ning
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
| | - Yan Li
- School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China.
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50
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Schwark AL, Stadler ZK. Should We Lower Our Threshold for Germline Genetic Assessment in Pancreatic Adenocarcinoma? JCO Precis Oncol 2018; 2:1-4. [DOI: 10.1200/po.17.00227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Alicia Latham Schwark
- Alicia Latham Schwark and Zsofia K. Stadler, Memorial Sloan Kettering Cancer Center; and Zsofia K. Stadler, Weill Cornell Medical College, New York, NY
| | - Zsofia K. Stadler
- Alicia Latham Schwark and Zsofia K. Stadler, Memorial Sloan Kettering Cancer Center; and Zsofia K. Stadler, Weill Cornell Medical College, New York, NY
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