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Voogd DWM, Lucassen MJJ, van der Noll R, Zielhuis SWJ, Boss D, Beijnen JH, Rosing H, Tibben M, Huitema ADR, Schellens JHM, Steeghs N. Phase I Study of Sorafenib Combined with Gemcitabine and Carboplatin in Patients with Advanced Solid Tumors. Oncol Ther 2025:10.1007/s40487-025-00340-8. [PMID: 40366624 DOI: 10.1007/s40487-025-00340-8] [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: 02/05/2025] [Accepted: 04/08/2025] [Indexed: 05/15/2025] Open
Abstract
INTRODUCTION A combination of targeted anticancer drugs with cytotoxic therapy can potentially overcome multidrug resistance. The multi-target kinase inhibitor sorafenib demonstrates synergistic activity when combined with chemotherapeutics in preclinical models. This phase I trial aimed to assess safety, tolerability, efficacy, and pharmacokinetics of sorafenib with gemcitabine and carboplatin. METHODS This single-center, open-label, dose-escalation and dose-expansion study included patients with advanced solid tumors considered for palliative treatment with gemcitabine and carboplatin. The maximum tolerated dose (MTD) was determined using a classic 3 + 3 dose-escalation design. Antitumor activity was evaluated every two treatment cycles. RESULTS In total, 45 patients received treatment. Of the patients, 49% (n = 22) were male, and median age was 58 years [range: 27-72 years]. After dose-escalation, sorafenib 400 mg once daily (q.d.) on days 1-21, gemcitabine 500 mg/m2 on day 1 and day 8 (D1D8), and carboplatin AUC3 on day 1 (D1) every 3 weeks (Q3W) were established as the MTD. Grade 4 treatment-related toxicities, all hematological, were seen in 22% of the patients. Frequently observed grade 3 adverse events were neutropenia (33%), thrombocytopenia (31%), leukopenia (16%), and fatigue (13%). Dose reductions were required in 33% of the patients across all dose levels. Disease control rate after 18 weeks was 50%. Median progression-free survival and overall survival were 5.4 months and 10.1 months, respectively. CONCLUSIONS A recommended phase 2 regimen of sorafenib 400 mg q.d. combined with gemcitabine 500 mg/m2 D1D8 and carboplatin AUC3 D1, Q3W showed a manageable toxicity profile. This combination could provide an effective treatment option for patients in whom other therapies have failed since antitumor activity was seen across heavily pretreated tumor types. Alternative dosing regimens should be studied to optimize the dosing schedule. TRIAL REGISTRATION EudraCT: 2007-004129-75.
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Affiliation(s)
- Daphne W M Voogd
- Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Merel J J Lucassen
- Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
| | - Ruud van der Noll
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Sybrand W J Zielhuis
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - David Boss
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos H Beijnen
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
| | - Hilde Rosing
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Matthijs Tibben
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Alwin D R Huitema
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Jan H M Schellens
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands
| | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
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Nair ST, Abhi C, Kamalasanan K, Pavithran K, Unni AR, Sithara MS, Sarma M, Mangalanandan TS. Pathophysiology-Driven Approaches for Overcoming Nanomedicine Resistance in Pancreatic Cancer. Mol Pharm 2024; 21:5960-5988. [PMID: 39561094 DOI: 10.1021/acs.molpharmaceut.4c00801] [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: 11/21/2024]
Abstract
Tumor heterogeneity poses a significant challenge in cancer therapy. To address this, we analyze pharmacotherapeutic challenges by categorizing them into static and dynamic barriers, reframing these challenges to improve drug delivery, efficacy, and the development of controlled-release nanomedicines (CRNMs). This pathophysiology-driven approach facilitates the design of novel therapeutics tailored to overcome obstacles in pancreatic ductal adenocarcinoma (PDAC) using nanotechnology. Advanced biomaterials in nanodrug delivery systems offer innovative solutions by combining controlled release, stimuli sensitivity, and smart design strategies. CRNMs are engineered to modulate spatiotemporal signaling and control drug release in PDAC, where resistance to conventional therapies is particularly high. This review explores pharmacokinetic considerations for nanomedicine design, RNA interference (RNAi) for stromal modulation, and the development of targeted nanomedicine strategies. Additionally, we highlight the limitations of current animal models in capturing the complexities of PDAC and discuss notable clinical failures, such as PEGylated hyaluronidase (Phase III HALO 109-301 trial) and evofosfamide (TH-302) with gemcitabine (MAESTRO trial), underscoring the need for improved models and treatment strategies. By targeting pathways like Notch and Hedgehog and incorporating stimuli-sensitive and pathway-modulating agents, CRNMs offer a promising avenue to enhance drug penetration and efficacy, reshaping the paradigm of pancreatic cancer treatment.
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Affiliation(s)
- Sreejith Thrivikraman Nair
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - C Abhi
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Kaladhar Kamalasanan
- Department of Pharmaceutics, Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - K Pavithran
- Department of Medical Oncology and Hematology, School of Medicine, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Ashok R Unni
- Department of Veterinary Medicine, Central Animal Facility, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - M S Sithara
- Department of Veterinary Medicine, Central Animal Facility, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - Manjit Sarma
- Department of Nuclear Medicine, Amrita School of Medicine, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
| | - T S Mangalanandan
- Department of Endocrinology, Amrita Institute of Medical Sciences and Research Centre, AIMS Health Sciences Campus, Amrita Vishwa Vidyapeetham, Kochi, Kerala 682041, India
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Wang Q, Cheng N, Wang W, Bao Y. Synergistic Action of Benzyl Isothiocyanate and Sorafenib in a Nanoparticle Delivery System for Enhanced Triple-Negative Breast Cancer Treatment. Cancers (Basel) 2024; 16:1695. [PMID: 38730647 PMCID: PMC11083210 DOI: 10.3390/cancers16091695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 04/23/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
Triple-negative breast cancer (TNBC) presents a therapeutic challenge due to its complex pathology and limited treatment options. Addressing this challenge, our study focuses on the effectiveness of combination therapy, which has recently become a critical strategy in cancer treatment, improving therapeutic outcomes and combating drug resistance and metastasis. We explored a novel combination therapy employing Benzyl isothiocyanate (BITC) and Sorafenib (SOR) and their nanoformulation, aiming to enhance therapeutic outcomes against TNBC. Through a series of in vitro assays, we assessed the cytotoxic effects of BITC and SOR, both free and encapsulated. The BITC-SOR-loaded nanoparticles (NPs) were synthesized using an amphiphilic copolymer, which demonstrated a uniform spherical morphology and favorable size distribution. The encapsulation efficiencies, as well as the sustained release profiles at varied pH levels, were quantified, revealing distinct kinetics that were well-modeled by the Korsmeyer-Peppas equation. The NP delivery system showed a marked dose-dependent cytotoxicity towards TNBC cells, with an IC50 of 7.8 μM for MDA-MB-231 cells, indicating improved efficacy over free drugs, while exhibiting minimal toxicity toward normal breast cells. Furthermore, the NPs significantly inhibited cell migration and invasion in TNBC models, surpassing the effects of free drugs. These findings underscore the potential of BITC-SOR-NPs as a promising therapeutic approach for TNBC, offering targeted delivery while minimizing systemic toxicity.
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Affiliation(s)
- Qi Wang
- Correspondence: (Q.W.); (Y.B.)
| | | | | | - Yongping Bao
- Norwich Medical School, University of East Anglia, Norwich NR4 7UQ, UK
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Myo Min KK, Ffrench CB, Jessup CF, Shepherdson M, Barreto SG, Bonder CS. Overcoming the Fibrotic Fortress in Pancreatic Ductal Adenocarcinoma: Challenges and Opportunities. Cancers (Basel) 2023; 15:2354. [PMID: 37190281 PMCID: PMC10137060 DOI: 10.3390/cancers15082354] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/06/2023] [Accepted: 04/14/2023] [Indexed: 05/17/2023] Open
Abstract
An overabundance of desmoplasia in the tumour microenvironment (TME) is one of the defining features that influences pancreatic ductal adenocarcinoma (PDAC) development, progression, metastasis, and treatment resistance. Desmoplasia is characterised by the recruitment and activation of fibroblasts, heightened extracellular matrix deposition (ECM) and reduced blood supply, as well as increased inflammation through an influx of inflammatory cells and cytokines, creating an intrinsically immunosuppressive TME with low immunogenic potential. Herein, we review the development of PDAC, the drivers that initiate and/or sustain the progression of the disease and the complex and interwoven nature of the cellular and acellular components that come together to make PDAC one of the most aggressive and difficult to treat cancers. We review the challenges in delivering drugs into the fortress of PDAC tumours in concentrations that are therapeutic due to the presence of a highly fibrotic and immunosuppressive TME. Taken together, we present further support for continued/renewed efforts focusing on aspects of the extremely dense and complex TME of PDAC to improve the efficacy of therapy for better patient outcomes.
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Affiliation(s)
- Kay K. Myo Min
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; (K.K.M.M.); (C.B.F.)
| | - Charlie B. Ffrench
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; (K.K.M.M.); (C.B.F.)
| | - Claire F. Jessup
- College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia
| | - Mia Shepherdson
- College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia
- Hepatopancreatobiliary & Liver Transplant Unit, Division of Surgery & Perioperative Medicine, Flinders Medical Centre, Bedford Park, SA 5042, Australia
| | - Savio George Barreto
- College of Medicine & Public Health, Flinders University, Bedford Park, SA 5042, Australia
- Hepatopancreatobiliary & Liver Transplant Unit, Division of Surgery & Perioperative Medicine, Flinders Medical Centre, Bedford Park, SA 5042, Australia
| | - Claudine S. Bonder
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia; (K.K.M.M.); (C.B.F.)
- Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia
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Nong S, Han X, Xiang Y, Qian Y, Wei Y, Zhang T, Tian K, Shen K, Yang J, Ma X. Metabolic reprogramming in cancer: Mechanisms and therapeutics. MedComm (Beijing) 2023; 4:e218. [PMID: 36994237 PMCID: PMC10041388 DOI: 10.1002/mco2.218] [Citation(s) in RCA: 75] [Impact Index Per Article: 37.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 01/22/2023] [Accepted: 01/30/2023] [Indexed: 03/29/2023] Open
Abstract
Cancer cells characterized by uncontrolled growth and proliferation require altered metabolic processes to maintain this characteristic. Metabolic reprogramming is a process mediated by various factors, including oncogenes, tumor suppressor genes, changes in growth factors, and tumor-host cell interactions, which help to meet the needs of cancer cell anabolism and promote tumor development. Metabolic reprogramming in tumor cells is dynamically variable, depending on the tumor type and microenvironment, and reprogramming involves multiple metabolic pathways. These metabolic pathways have complex mechanisms and involve the coordination of various signaling molecules, proteins, and enzymes, which increases the resistance of tumor cells to traditional antitumor therapies. With the development of cancer therapies, metabolic reprogramming has been recognized as a new therapeutic target for metabolic changes in tumor cells. Therefore, understanding how multiple metabolic pathways in cancer cells change can provide a reference for the development of new therapies for tumor treatment. Here, we systemically reviewed the metabolic changes and their alteration factors, together with the current tumor regulation treatments and other possible treatments that are still under investigation. Continuous efforts are needed to further explore the mechanism of cancer metabolism reprogramming and corresponding metabolic treatments.
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Affiliation(s)
- Shiqi Nong
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Xiaoyue Han
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Yu Xiang
- Department of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Yuran Qian
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Yuhao Wei
- Department of Clinical MedicineWest China School of MedicineWest China HospitalSichuan UniversityChengduSichuanChina
| | - Tingyue Zhang
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Keyue Tian
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
| | - Kai Shen
- Department of OncologyFirst Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Jing Yang
- State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐sen University Cancer CenterGuangzhouChina
| | - Xuelei Ma
- State Key Laboratory of Oral DiseasesWest China Hospital of StomatologyWest China School of StomatologyNational Clinical Research Center for Oral DiseasesSichuan UniversityChengduSichuanChina
- Department of Biotherapy and Cancer CenterState Key Laboratory of BiotherapyCancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
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Liu Q, Li R, Wu H, Liang Z. A novel cuproptosis-related gene model predicts outcomes and treatment responses in pancreatic adenocarcinoma. BMC Cancer 2023; 23:226. [PMID: 36894917 PMCID: PMC9999523 DOI: 10.1186/s12885-023-10678-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 02/24/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Cuproptosis is recently emerging as a hot spot in cancer research. However, its role in pancreatic adenocarcinoma (PAAD) has not yet been clarified. This study aimed to explore the prognostic and therapeutic implications of cuproptosis-related genes in PAAD. METHODS Two hundred thirteen PAAD samples from the International Cancer Genome Consortium (ICGC) were split into training and validation sets in the ratio of 7:3. The Cox regression analyses generated a prognostic model using the ICGC cohort for training (n = 152) and validation (n = 61). The model was externally tested on the Gene Expression Omnibus (GEO) (n = 80) and The Cancer Genome Atlas (TCGA) datasets (n = 176). The clinical characteristics, molecular mechanisms, immune landscape, and treatment responses in model-defined subgroups were explored. The expression of an independent prognostic gene TSC22D2 was confirmed by public databases, real-time quantitative PCR (RT-qPCR), western blot (WB), and immunohistochemistry (IHC). RESULTS A prognostic model was established based on three cuproptosis-related genes (TSC22D2, C6orf136, PRKDC). Patients were stratified into high- and low-risk groups using the risk score based on this model. PAAD patients in the high-risk group had a worse prognosis. The risk score was statistically significantly correlated with most clinicopathological characteristics. The risk score based on this model was an independent predictor of overall survival (OS) (HR = 10.7, p < 0.001), and was utilized to create a scoring nomogram with excellent prognostic value. High-risk patients had a higher TP53 mutation rate and a superior response to multiple targeted therapies and chemotherapeutic drugs, but might obtain fewer benefits from immunotherapy. Moreover, elevated TSC22D2 expression was discovered to be an independent prognostic predictor for OS (p < 0.001). Data from public databases and our own experiments showed that TSC22D2 expression was significantly higher in pancreatic cancer tissues/cells compared to normal tissues/cells. CONCLUSION This novel model based on cuproptosis-related genes provided a robust biomarker for predicting the prognosis and treatment responses of PAAD. The potential roles and underlying mechanisms of TSC22D2 in PAAD need further explored.
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Affiliation(s)
- Qixian Liu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Ruiyu Li
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Huanwen Wu
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
| | - Zhiyong Liang
- Molecular Pathology Research Center, Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China.
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Research advances and treatment perspectives of pancreatic adenosquamous carcinoma. Cell Oncol (Dordr) 2023; 46:1-15. [PMID: 36316580 DOI: 10.1007/s13402-022-00732-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2022] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND As a malignant tumor, pancreatic cancer has an extremely low overall 5-year survival rate. Pancreatic adenosquamous carcinoma (PASC), a rare pancreatic malignancy, owns clinical presentation similar to pancreatic ductal adenocarcinoma (PDAC), which is the most prevalent pancreatic cancer subtype. PASC is generally defined as a pancreatic tumor consisting mainly of adenocarcinoma tissue and squamous carcinoma tissue. Compared with PDAC, PASC has a higher metastatic potential and worse prognosis, and lacks of effective treatment options to date. However, the pathogenesis and treatment of PASC are not yet clear and are accompanied with difficulties. CONCLUSION The present paper systematically summarizes the possible pathogenesis, diagnosis methods, and further suggests potential new treatment directions through reviewing research results of PASC, including the clinical manifestations, pathological manifestation, the original hypothesis of squamous carcinoma and the potential regulatory mechanism. In short, the present paper provides a systematic review of the research progress and new ideas for the development mechanism and treatment of PASC.
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Wang Q, Wang J, Yan H, Li Z, Wang K, Kang F, Tian J, Zhao X, Yun SH. An ultra-small bispecific protein augments tumor penetration and treatment for pancreatic cancer. Eur J Nucl Med Mol Imaging 2023; 50:1765-1779. [PMID: 36692541 DOI: 10.1007/s00259-023-06115-5] [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: 10/21/2022] [Accepted: 01/11/2023] [Indexed: 01/25/2023]
Abstract
PURPOSE The once highly anticipated antibody-based pathway-targeted therapies have not achieved promising outcomes for deadly pancreatic ductal adenocarcinoma (PDAC), mainly due to drugs' low intrinsic anticancer activity and poor penetration across the dense physiological barrier. This study aims to develop an ultra-small-sized, EGFR/VEGF bispecific therapeutic protein to largely penetrate deep tumor tissue and effectively inhibit PDAC tumor growth in vivo. METHODS The bispecific protein, Bi-fp50, was constructed by a typical synthetic biology method and labeled with fluorescent dyes for in vitro and in vivo imaging. Physicochemical properties, protein dual-binding affinity, and specificity of the Bi-fp50 were evaluated in several PDAC cell lines. In vitro quantitatively and qualitatively anticancer activity of Bi-fp50 was assessed by live/dead staining, MTT assay, and flow cytometry. In vivo pharmacokinetic and biodistribution were evaluated using blood biopsy samples and near-infrared fluorescence imaging. In vivo real-time tracking of Bi-fp50 in the local tumor was conducted by fibered confocal fluorescence microscopy. The subcutaneous PDAC tumor model was used to assess the in vivo antitumor effect of Bi-fp50. RESULTS Bi-fp50 with an ultra-small size of 50 kDa (5 ~ 6 nm) showed an excellent binding ability to VEGF and EGFR simultaneously and had enhanced, accumulated binding capability for Bxpc3 PDAC cells compared with anti-VEGF scFv and anti-EGFR scFv alone. Additionally, bi-fp50 significantly inhibited the proliferation and growth of Bxpc3 and Aspc1 PDAC cells even under a relatively low concentration (0.3 µM). It showed synergistically enhanced therapeutic effects relative to two individual scFv and Bi-fp50x control in vitro. The half-life of blood clearance of Bi-fp50 was 4.33 ± 0.23 h. After intravenous injection, Bi-fp50 gradually penetrated the deep tumor, widely distributed throughout the whole tissue, and primarily enriched in the tumor with nearly twice the accumulation than scFv2 in the orthotopic PDAC tumor model. Furthermore, the Bi-fp50 protein could induce broad apoptosis in the whole tumor and significantly inhibited tumor growth 3 weeks after injection in vivo without other noticeable side effects. CONCLUSION The proof-of-concept study demonstrated that the ultra-small-sized, bispecific protein Bi-fp50 could be a potential tumor suppressor and an efficient, safe theranostic tool for treating PDAC tumors.
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Affiliation(s)
- Qian Wang
- Department of Diagnostic Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Acadamy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Jingyun Wang
- School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, People's Republic of China
| | - Hao Yan
- Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, Cambridge, MA, 02139, USA. .,Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, People's Republic of China.
| | - Zheng Li
- Yi-Chuang Institute of Biotechnology Industry, Beijing, 101111, People's Republic of China
| | - Kun Wang
- CAS Key Laboratory of Molecular Imaging, Institute of Automation and Chinese Academy of Sciences, Beijing, 100190, People's Republic of China
| | - Feiyu Kang
- Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, People's Republic of China
| | - Jie Tian
- CAS Key Laboratory of Molecular Imaging, Institute of Automation and Chinese Academy of Sciences, Beijing, 100190, People's Republic of China.
| | - Xinming Zhao
- Department of Diagnostic Imaging, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Acadamy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China.
| | - Seok-Hyun Yun
- Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, Cambridge, MA, 02139, USA
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Kim HJ, Ji YR, Lee YM. Crosstalk between angiogenesis and immune regulation in the tumor microenvironment. Arch Pharm Res 2022; 45:401-416. [PMID: 35759090 PMCID: PMC9250479 DOI: 10.1007/s12272-022-01389-z] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/25/2022] [Indexed: 12/15/2022]
Abstract
Cancer creates a complex tumor microenvironment (TME) composed of immune cells, stromal cells, blood vessels, and various other cellular and extracellular elements. It is essential for the development of anti-cancer combination therapies to understand and overcome this high heterogeneity and complexity as well as the dynamic interactions between them within the TME. Recent treatment strategies incorporating immune-checkpoint inhibitors and anti-angiogenic agents have brought many changes and advances in clinical cancer treatment. However, there are still challenges for immune suppressive tumors, which are characterized by a lack of T cell infiltration and treatment resistance. In this review, we will investigate the crosstalk between immunity and angiogenesis in the TME. In addition, we will look at strategies designed to enhance anti-cancer immunity, to convert "immune suppressive tumors" into "immune activating tumors," and the mechanisms by which these strategies enhance effector immune cell infiltration.
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Affiliation(s)
- Hei Jung Kim
- Vessel-Organ Interaction Research Center, VOICE (MRC), Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea
| | - Young Rae Ji
- National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, USA
| | - You Mie Lee
- Vessel-Organ Interaction Research Center, VOICE (MRC), Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea.
- Department of Molecular Pathophysiology, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea.
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Zhao X, Li Z, Gu Z. A new era: tumor microenvironment in chemoresistance of pancreatic cancer. JOURNAL OF CANCER SCIENCE AND CLINICAL THERAPEUTICS 2022; 6:61-86. [PMID: 35187493 DOI: 10.26502/jcsct.5079146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a solid malignant tumor with an extremely poor prognosis. Gemcitabine (GEM)-based chemotherapy remains one of the most important treatment choices for PDAC. However, either as monotherapy or as a part of the combination chemotherapy, GEM achieved only limited success in improving the survival of patients with advanced PDAC, primarily due to GEM resistance. PDAC is characterized by an extensive desmoplasia in the tumor microenvironment (TME). Increasing evidence indicates that this fibrotic TME not only actively participates in the tumor growth and spread of PDAC but also contributes to the induction of GEM resistance. Here we review the current advances of how TME components are involved in the induction of GEM resistance.
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Affiliation(s)
- Xueping Zhao
- School of Life Science and Biopharmaceutical, Shenyang Pharmaceutical University, Shenyang, China
| | - Zongze Li
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zongting Gu
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Rajpurohit T, Bhattacharya S. Moving Towards Dawn: KRas Signaling and Treatment in Pancreatic Ductal Adenocarcinoma. Curr Mol Pharmacol 2022; 15:904-928. [PMID: 35088684 DOI: 10.2174/1874467215666220128161647] [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: 07/26/2021] [Revised: 10/20/2021] [Accepted: 11/17/2021] [Indexed: 12/24/2022]
Abstract
"Pancreatic ductal adenocarcinoma (PDAC)" is robust, nearly clueless, and all-around deadly among all tumors. Below 10 %, the general 5-year endurance period has remained adamantly unaltered in the last 30 years, regardless of enormous clinical and therapeutic endeavors. The yearly number of deaths is more than the number of recently analyzed cases. Not a classic one, but "Carbohydrate Antigen CA19- 9" remains the prevailing tool for diagnosis. MicroRNAs and non-invasive techniques are now incorporated for the effective prognosis of PDAC than just CA19-9. Mutated "Rat sarcoma virus Ras" conformation "V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog KRas" is 95 % accountable for PDAC, and its active (GTP-bound) formation activates signaling cascade comprising "Rapidly accelerated fibrosarcoma Raf"/"Mitogen-activated protein kinase MEK"/ "Extracellular signal-regulated kinase ERK" with "Phosphoinositide 3-kinase PI3K"/ "protein kinase B Akt"/ "mammalian target of rapamycin mTOR" pathways. KRas has acquired the label of 'undruggable' since the crosstalk in the nexus of pathways compensates for Raf and PI3K signaling cascade blocking. It is arduous to totally regulate KRascoordinated PDAC with traditional medicaments like "gemcitabine GEM" plus nabpaclitaxel/ FOLFIRINOX. For long-haul accomplishments aiming at KRas, future endeavors should be directed to combinatorial methodologies to adequately block KRas pathways at different standpoints. Currently they are contributing to healing PDAC. In this review article, we outline the function of KRas in carcinogenesis in PDAC, its signaling cascade, former techniques utilized in hindering Kras, current and future possibilities for targeting Kras.
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Affiliation(s)
- Tarun Rajpurohit
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India
| | - Sankha Bhattacharya
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra 425405, India
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12
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Blomstrand H, Batra A, Cheung WY, Elander NO. Real-world evidence on first- and second-line palliative chemotherapy in advanced pancreatic cancer. World J Clin Oncol 2021; 12:787-799. [PMID: 34631442 PMCID: PMC8479347 DOI: 10.5306/wjco.v12.i9.787] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 05/09/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
In spite of recent diagnostic and therapeutic advances, the prognosis of pancreatic ductal adenocarcinoma (PDAC) remains very poor. As most patients are not amenable to curative intent treatments, optimized palliative management is highly needed. One key question is to what extent promising results produced by randomized controlled trials (RCTs) correspond to clinically meaningful outcomes in patients treated outside the strict frames of a clinical trial. To answer such questions, real-world evidence is necessary. The present paper reviews and discusses the current literature on first- and second-line palliative chemotherapy in PDAC. Notably, a growing number of studies report that the outcomes of the two predominant first-line multidrug regimens, i.e. gemcitabine plus nab-paclitaxel (GnP) and folfirinox (FFX), is similar in RCTs and real-life populations. Outcomes of second-line therapy following failure of first-line regimens are still dismal, and considerable uncertainty of the optimal management remains. Additional RCTs and real-world evidence studies focusing on the optimal treatment sequence, such as FFX followed by GnP or vice versa, are urgently needed. Finally, the review highlights the need for prognostic and predictive biomarkers to inform clinical decision making and enable personalized management in advanced PDAC.
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Affiliation(s)
- Hakon Blomstrand
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping 58185, Sweden
| | - Atul Batra
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Winson Y Cheung
- Department of Oncology, University of Calgary, Calgary T2N 4N1, Canada
| | - Nils Oskar Elander
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping 58185, Sweden
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13
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Yang HH, Liu JW, Lee JH, Harn HJ, Chiou TW. Pancreatic Adenocarcinoma Therapeutics Targeting RTK and TGF Beta Receptor. Int J Mol Sci 2021; 22:ijms22158125. [PMID: 34360896 PMCID: PMC8348294 DOI: 10.3390/ijms22158125] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 06/28/2021] [Accepted: 07/26/2021] [Indexed: 12/21/2022] Open
Abstract
Despite the improved overall survival rates in most cancers, pancreatic cancer remains one of the deadliest cancers in this decade. The rigid microenvironment, which majorly comprises cancer-associated fibroblasts (CAFs), plays an important role in the obstruction of pancreatic cancer therapy. To overcome this predicament, the signaling of receptor tyrosine kinases (RTKs) and TGF beta receptor (TGFβR) in both pancreatic cancer cell and supporting CAF should be considered as the therapeutic target. The activation of receptors has been reported to be aberrant to cell cycle regulation, and signal transduction pathways, such as growth-factor induced proliferation, and can also influence the apoptotic sensitivity of tumor cells. In this article, the regulation of RTKs/TGFβR between pancreatic ductal adenocarcinoma (PDAC) and CAFs, as well as the RTKs/TGFβR inhibitor-based clinical trials on pancreatic cancer are reviewed.
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Affiliation(s)
- Hsin-Han Yang
- Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan;
| | - Jen-Wei Liu
- Everfront Biotech Inc., New Taipei City 221, Taiwan; (J.-W.L.); (J.-H.L.)
| | - Jui-Hao Lee
- Everfront Biotech Inc., New Taipei City 221, Taiwan; (J.-W.L.); (J.-H.L.)
| | - Horng-Jyh Harn
- Bioinnovation Center, Tzu Chi Foundation, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan
- Department of Pathology, Buddhist Tzu Chi General Hospital, Tzu Chi University, Hualien 970, Taiwan
- Correspondence: (H.-J.H.); (T.-W.C.)
| | - Tzyy-Wen Chiou
- Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien 974, Taiwan;
- Correspondence: (H.-J.H.); (T.-W.C.)
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14
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Schiliro C, Firestein BL. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells 2021; 10:cells10051056. [PMID: 33946927 PMCID: PMC8146072 DOI: 10.3390/cells10051056] [Citation(s) in RCA: 305] [Impact Index Per Article: 76.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 04/27/2021] [Accepted: 04/28/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.
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Affiliation(s)
- Chelsea Schiliro
- Cell and Developmental Biology Graduate Program and Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA;
| | - Bonnie L. Firestein
- Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA
- Correspondence: ; Tel.: +1-848-445-8045
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15
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Gu ZT, Li ZZ, Wang CF. Advances in research of extracellular mechanisms underlying gemcitabine resistance in pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2021; 29:421-434. [DOI: 10.11569/wcjd.v29.i8.421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a solid malignant tumor with the worst prognosis worldwide, and about 90% of cases are pancreatic ductal adenocarcinoma (PDAC). Although surgical resection is the only potential way to cure PDAC, the overall survival rate after surgery is still not optimistic. Consequently, gemcitabine (GEM)-based chemotherapy is still one of the most important treatment options for PDAC. However, the survival improvement by GEM monotherapy for advanced PDAC is very limited, and GEM resistance is the key reason. The mechanism underlying gemcitabine resistance is complex and still unclear in PDAC. The extensive and dense fibrous mesenchyme in the tumor microenvironment (TME) is an important feature of PDAC. More and more evidence has shown that TME is not only an active participant in tumor growth and spread, but also a contributor to the induction of GEM resistance. This article will review the recent advances in the understanding of the cellular and molecular mechanisms underlying GEM resistance in PDAC, and discuss potential GEM chemosensitization strategies, in order to improve the effective rate of chemotherapy and the outcome.
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Affiliation(s)
- Zong-Ting Gu
- Cheng-Feng Wang, State Key Laboratory of Molecular Oncology & Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zong-Ze Li
- Cheng-Feng Wang, State Key Laboratory of Molecular Oncology & Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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16
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Mechanisms of drug resistance of pancreatic ductal adenocarcinoma at different levels. Biosci Rep 2021; 40:225827. [PMID: 32677676 PMCID: PMC7396420 DOI: 10.1042/bsr20200401] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 07/05/2020] [Accepted: 07/16/2020] [Indexed: 12/16/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.
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17
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Liu X, Li Z, Wang Y. Advances in Targeted Therapy and Immunotherapy for Pancreatic Cancer. Adv Biol (Weinh) 2021; 5:e1900236. [PMID: 33729700 DOI: 10.1002/adbi.201900236] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 08/19/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is a highly aggressive malignancy with an overall 5-year survival rate of <6% due to therapeutic resistance and late-stage diagnosis. These statistics have not changed despite 50 years of research and therapeutic development. Pancreatic cancer is predicted to become the second leading cause of cancer mortality by the year 2030. Currently, the treatment options for pancreatic cancer are limited. This disease is usually diagnosed at a late stage, which prevents curative surgical resection. Chemotherapy is the most frequently used approach for pancreatic cancer treatment and has limited effects. In many other cancer types, targeted therapy and immunotherapy have made great progress and have been shown to be very promising prospects; these treatments also provide hope for pancreatic cancer. The need for research on targeted therapy and immunotherapy is pressing due to the poor prognosis of pancreatic cancer, and in recent years, there have been some breakthroughs for targeted therapy and immunotherapy in pancreatic cancer. This review summarizes the current preclinical and clinical studies of targeted therapy and immunotherapy for pancreatic cancer and ends by describing the challenges and outlook.
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Affiliation(s)
- Xiaoxiao Liu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Zhang Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuexiang Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, SINH - Changzheng Hospital Joint Center for Translational Medicine, Institutes for Translational Medicine (CAS-SMMU), Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
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18
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Al-Share B, Hammad N, Diab M. Pancreatic adenocarcinoma: molecular drivers and the role of targeted therapy. Cancer Metastasis Rev 2021; 40:355-371. [PMID: 33398620 DOI: 10.1007/s10555-020-09948-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/15/2020] [Indexed: 01/05/2023]
Abstract
Prognosis from pancreatic ductal adenocarcinoma (PDAC) continues to be poor despite the many efforts channeled to improve its management. Although the mainstay treatment is still traditional chemotherapy, recent advances highlighted a promising potential for targeted therapy in the management of this disease. Those advances emphasize the significance of timely genomic profiling of tumor tissue as well as germline testing of patients to identify potential markers of targeted therapy. While targeted therapy is reserved for a relatively small subset of patients with PDAC, ongoing research is uncovering additional markers, and targeted agents, that will hopefully translate to better outcomes for patients.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Wayne State University, Karmanos Cancer Institute, Detroit, MI, USA
| | - Nour Hammad
- Department of Oncology, Ascension Providence Hospital and Medical Center/Michigan State University/Collage of Human Medicine, Southfield, MI, USA
| | - Maria Diab
- Department of Oncology, Emory University, Atlanta, GA, USA.
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19
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Uprety D, Adjei AA. KRAS: From undruggable to a druggable Cancer Target. Cancer Treat Rev 2020; 89:102070. [DOI: 10.1016/j.ctrv.2020.102070] [Citation(s) in RCA: 171] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/04/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
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20
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Profound Reprogramming towards Stemness in Pancreatic Cancer Cells as Adaptation to AKT Inhibition. Cancers (Basel) 2020; 12:cancers12082181. [PMID: 32764385 PMCID: PMC7464748 DOI: 10.3390/cancers12082181] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 07/30/2020] [Accepted: 08/03/2020] [Indexed: 12/17/2022] Open
Abstract
Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression and a key pharmacological target. The mechanisms of adaptation to long-term silencing of AKT isoforms of human and mouse pancreatic adenocarcinoma cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG upregulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.
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21
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De Jesus-Acosta A, Narang A, Mauro L, Herman J, Jaffee EM, Laheru DA. Carcinoma of the Pancreas. ABELOFF'S CLINICAL ONCOLOGY 2020:1342-1360.e7. [DOI: 10.1016/b978-0-323-47674-4.00078-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res 2019; 150:104511. [DOI: 10.1016/j.phrs.2019.104511] [Citation(s) in RCA: 358] [Impact Index Per Article: 59.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/19/2019] [Accepted: 10/23/2019] [Indexed: 12/24/2022]
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Abstract
OBJECTIVES We evaluated how well phase II trials in locally advanced and metastatic pancreatic cancer (LAMPC) meet current recommendations for trial design. METHODS We conducted a systematic review of phase II first-line treatment trial for LAMPC. We assessed baseline characteristics, type of comparison, and primary end point to examine adherence to the National Cancer Institute recommendations for trial design. RESULTS We identified 148 studies (180 treatment arms, 7505 participants). Forty-seven (32%) studies adhered to none of the 5 evaluated National Cancer Institute recommendations, 62 (42%) followed 1, 31 (21%) followed 2, and 8 (5%) followed 3 recommendations. Studies varied with respect to the proportion of patients with good performance status (range, 0%-80%) and locally advanced disease (range, 14%-100%). Eighty-two (55%) studies concluded that investigational agents should progress to phase III testing; of these, 24 (16%) had documented phase III trials. Three (8%) phase III trials demonstrated clinically meaningful improvements for investigational agents. One of 38 phase II trials that investigated biological investigational agents was enriched for a biomarker. CONCLUSIONS Phase II trials do not conform well to current recommendations for trial design in LAMPC.
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Farran B, Nagaraju GP. The dynamic interactions between the stroma, pancreatic stellate cells and pancreatic tumor development: Novel therapeutic targets. Cytokine Growth Factor Rev 2019; 48:11-23. [PMID: 31331827 DOI: 10.1016/j.cytogfr.2019.07.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Revised: 07/09/2019] [Accepted: 07/11/2019] [Indexed: 02/06/2023]
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25
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Lakkakula BVKS, Farran B, Lakkakula S, Peela S, Yarla NS, Bramhachari PV, Kamal MA, Saddala MS, Nagaraju GP. Small molecule tyrosine kinase inhibitors and pancreatic cancer-Trials and troubles. Semin Cancer Biol 2019; 56:149-167. [PMID: 30314681 DOI: 10.1016/j.semcancer.2018.09.011] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 09/18/2018] [Accepted: 09/29/2018] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) is an aggressive carcinoma and the fourth cause of cancer deaths in Western countries. Although surgery is the most effective therapeutic option for PC, the management of unresectable, locally advanced disease is highly challenging. Our improved understanding of pancreatic tumor biology and associated pathways has led to the development of various treatment modalities that can control the metastatic spread of PC. This review intends to present trials of small molecule tyrosine kinase inhibitors (TKIs) in PC management and the troubles encountered due to inevitable acquired resistance to TKIs.
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Affiliation(s)
| | - Batoul Farran
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA
| | - Saikrishna Lakkakula
- Department of Zoology, Visvodaya Government Degree College, Venkatagiri, AP-524132, India
| | - Sujatha Peela
- Department of Biotechnology, Dr.B.R.Ambedkar University, Srikakulam, Andhra Pradesh, India
| | - Nagendra Sastry Yarla
- Dr. LV Prasad Diagnostics and Research Laboratory, Khairtabad, Hyderabad, AP- 500004, India
| | | | - Mohammad Amjad Kamal
- King Fahd Medical Research Center, King Abdulaziz University, P. O. Box 80216, Jeddah 21589, Saudi Arabia; Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia; Novel Global Community Educational Foundation, Australia
| | | | - Ganji Purnachandra Nagaraju
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA-30322, USA.
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26
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van Mackelenbergh MG, Stroes CI, Spijker R, van Eijck CHJ, Wilmink JW, Bijlsma MF, van Laarhoven HWM. Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:E588. [PMID: 31035512 PMCID: PMC6562438 DOI: 10.3390/cancers11050588] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/19/2019] [Accepted: 04/22/2019] [Indexed: 12/14/2022] Open
Abstract
The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90-1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26-1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.
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Affiliation(s)
- Madelaine G van Mackelenbergh
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Charlotte I Stroes
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - René Spijker
- Medical Library, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Cochrane Netherlands, Julius Center, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
| | - Casper H J van Eijck
- Department of Surgery, Erasmus MC, Dr. Molewaterplein 40, 3015GD Rotterdam, The Netherlands.
| | - Johanna W Wilmink
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Maarten F Bijlsma
- Laboratory of Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
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Jagust P, de Luxán-Delgado B, Parejo-Alonso B, Sancho P. Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells. Front Pharmacol 2019; 10:203. [PMID: 30967773 PMCID: PMC6438930 DOI: 10.3389/fphar.2019.00203] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 02/18/2019] [Indexed: 02/02/2023] Open
Abstract
Cancer heterogeneity constitutes the major source of disease progression and therapy failure. Tumors comprise functionally diverse subpopulations, with cancer stem cells (CSCs) as the source of this heterogeneity. Since these cells bear in vivo tumorigenicity and metastatic potential, survive chemotherapy and drive relapse, its elimination may be the only way to achieve long-term survival in patients. Thanks to the great advances in the field over the last few years, we know now that cellular metabolism and stemness are highly intertwined in normal development and cancer. Indeed, CSCs show distinct metabolic features as compared with their more differentiated progenies, though their dominant metabolic phenotype varies across tumor entities, patients and even subclones within a tumor. Following initial works focused on glucose metabolism, current studies have unveiled particularities of CSC metabolism in terms of redox state, lipid metabolism and use of alternative fuels, such as amino acids or ketone bodies. In this review, we describe the different metabolic phenotypes attributed to CSCs with special focus on metabolism-based therapeutic strategies tested in preclinical and clinical settings.
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Affiliation(s)
- Petra Jagust
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Beatriz de Luxán-Delgado
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Beatriz Parejo-Alonso
- Traslational Research Unit, Hospital Universitario Miguel Servet, Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain
| | - Patricia Sancho
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Traslational Research Unit, Hospital Universitario Miguel Servet, Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain
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Cortes E, Lachowski D, Robinson B, Sarper M, Teppo JS, Thorpe SD, Lieberthal TJ, Iwamoto K, Lee DA, Okada-Hatakeyama M, Varjosalo MT, Del Río Hernández AE. Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival. EMBO Rep 2019; 20:e46557. [PMID: 30538116 PMCID: PMC6322388 DOI: 10.15252/embr.201846557] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 10/19/2018] [Accepted: 10/23/2018] [Indexed: 12/25/2022] Open
Abstract
The tumor microenvironment is fundamental to cancer progression, and the influence of its mechanical properties is increasingly being appreciated. Tamoxifen has been used for many years to treat estrogen-positive breast cancer. Here we report that tamoxifen regulates the level and activity of collagen cross-linking and degradative enzymes, and hence the organization of the extracellular matrix, via a mechanism involving both the G protein-coupled estrogen receptor (GPER) and hypoxia-inducible factor-1 alpha (HIF-1A). We show that tamoxifen reduces HIF-1A levels by suppressing myosin-dependent contractility and matrix stiffness mechanosensing. Tamoxifen also downregulates hypoxia-regulated genes and increases vascularization in PDAC tissues. Our findings implicate the GPER/HIF-1A axis as a master regulator of peri-tumoral stromal remodeling and the fibrovascular tumor microenvironment and offer a paradigm shift for tamoxifen from a well-established drug in breast cancer hormonal therapy to an alternative candidate for stromal targeting strategies in PDAC and possibly other cancers.
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MESH Headings
- Adenocarcinoma/drug therapy
- Adenocarcinoma/genetics
- Adenocarcinoma/pathology
- Animals
- Carcinoma, Pancreatic Ductal/drug therapy
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Cell Line, Tumor
- Cell Survival/drug effects
- Cellular Reprogramming/drug effects
- Fibroblasts/drug effects
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Mice
- Myosins/genetics
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- Receptors, Estrogen/genetics
- Receptors, G-Protein-Coupled/genetics
- Signal Transduction/drug effects
- Tamoxifen/administration & dosage
- Tumor Microenvironment/drug effects
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Affiliation(s)
- Ernesto Cortes
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK
| | - Dariusz Lachowski
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK
| | - Benjamin Robinson
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK
| | - Muge Sarper
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK
| | - Jaakko S Teppo
- Institute of Biotechnology, University of Helsinki, Helsinki, Finland
| | - Stephen D Thorpe
- Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, UK
| | - Tyler J Lieberthal
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK
| | - Kazunari Iwamoto
- Laboratory of Cell Systems, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan
| | - David A Lee
- Institute of Bioengineering, School of Engineering and Materials Science, Queen Mary University of London, London, UK
| | - Mariko Okada-Hatakeyama
- Laboratory of Cell Systems, Institute for Protein Research, Osaka University, Suita, Osaka, Japan
- Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, Japan
| | | | - Armando E Del Río Hernández
- Cellular and Molecular Biomechanics Laboratory, Department of Bioengineering, Imperial College London, London, UK
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29
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Diab M, Azmi A, Mohammad R, Philip PA. Pharmacotherapeutic strategies for treating pancreatic cancer: advances and challenges. Expert Opin Pharmacother 2018; 20:535-546. [PMID: 30592647 DOI: 10.1080/14656566.2018.1561869] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Despite many efforts to improve the outcome of pancreatic ductal adenocarcinoma (PDAC), its prognosis remains poor, which is mostly related to late diagnosis and drug resistance. Improving systemic therapy is considered the major challenge in improving the outcome of this disease. AREAS COVERED This review covers novel chemotherapy and targeted agents in the treatment of PDAC, with a focus on advanced stage disease. EXPERT OPINION Current frontline therapies used in the treatment of patients with PDAC with favorable performance status are gemcitabine (GEM) and nab-paclitaxel or 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). PDAC has a number of genetic mutations that may explain its biological behavior, such as KRAS, p53 and CDK2NA, which occur in more than 90% of cases. Unfortunately, to this day, a specific targeting agent to any of those frequent gene mutations is lacking. Emerging areas of targeted therapies include the DNA repair, stroma, metabolism, and stem cells. Immunotherapy with either vaccines or immune checkpoint inhibitors has not produced any significant improvements in outcome of PDAC. Incorporating different approaches in therapy, including conventional, immunological, and others, is key in offering patients with the best possible care.
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Affiliation(s)
- Maria Diab
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Asfar Azmi
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Ramzi Mohammad
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA
| | - Philip A Philip
- a Department of Oncology, Karmanos Cancer institute , Wayne State University , Detroit , MI , USA.,b Department of Pharmacology, School of Medicine , Wayne State University , Detroit , MI , USA
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30
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Barati Bagherabad M, Afzaljavan F, ShahidSales S, Hassanian SM, Avan A. Targeted therapies in pancreatic cancer: Promises and failures. J Cell Biochem 2018; 120:2726-2741. [PMID: 28703890 DOI: 10.1002/jcb.26284] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 07/11/2018] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incidence rate nearly equal to its mortality rate. The poor prognosis of the disease can be explained by the absence of effective biomarkers for screening and early detection, together with the aggressive behavior and resistance to the currently available chemotherapy. The therapeutic failure can also be attributed to the inter-/intratumor genetic heterogeneity and the abundance of tumor stroma that occupies the majority of the tumor mass. Gemcitabine is used in the treatment of PDAC; however, the response rate is less than 12%. A recent phase III trial revealed that the combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin could be an option for the treatment of metastatic PDAC patients with good performance status, although these approaches can result in high toxicity level. Further investigations are required to develop innovative anticancer agents that either improve gemcitabine activity, within novel combinatorial approaches or acts with a better efficacy than gemcitabine. The aim of the current review is to give an overview of preclinical and clinical studies targeting key dysregulated signaling pathways in PDAC.
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Affiliation(s)
- Matineh Barati Bagherabad
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fahimeh Afzaljavan
- Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodabeh ShahidSales
- Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic syndrome Research center, Mashhad University of Medical Sciences, Mashhad, Iran.,Molecular Medicine group, Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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31
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Park S, Kim D, Wu G, Jung H, Park JA, Kwon HJ, Lee Y. A peptide-CpG-DNA-liposome complex vaccine targeting TM4SF5 suppresses growth of pancreatic cancer in a mouse allograft model. Onco Targets Ther 2018; 11:8655-8672. [PMID: 30584324 PMCID: PMC6284540 DOI: 10.2147/ott.s186606] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background Patients with pancreatic cancer have a poor prognosis and are usually diagnosed at a late stage. Because TM4SF5 is known to be overexpressed in hepatocellular carcinoma, colon cancer, and pancreatic cancer, it is considered as one of the candidate molecular targets for an anticancer strategies. Purpose The purpose of this study was to evaluate possible utility of TM4SF5 to treat pancreatic cancer using a mouse allograft model. Materials and methods We analyzed expression of TM4SF5 in pancreatic cancer tissues using immunohistochemistry. We established a mouse pancreatic cancer cell line stably expressing TM4SF5 and identified the effect of TM4SF5 expression in vitro. We used the CpG-DNA-peptide-liposome complex as a peptide vaccine and investigated antitumor effects of the vaccine in a mouse model with TM4SF5 expressing pancreatic cells. To investigate the function of produced antibody, we evaluated effects of the anti-TM4SF5 monoclonal antibody in vitro in terms of cell growth and migration properties. Results Immunohistochemical analysis showed that 36.4% of pancreatic cancer tissue samples expressed TM4SF5. Expression of TM4SF5 induced increased cell proliferation and motility in vitro. Injection of the TM4SF5 peptide vaccine induced the production of anti-hTM4SF5 antibodies and reduced the growth of pancreatic tumors in mice established by subcutaneous injection of the TM4SF5-expressing mouse pancreatic cancer cell line. The treatment of TM4SF5-expressing cells with the anti-hTM4SF5 monoclonal antibody reduced cell growth, modulated the expression of the epithelial–mesenchymal transition markers Vimentin and E-cadherin, and decreased cell motility in vitro. Conclusion Our results showed that the TM4SF5 peptide vaccine had a protective effect against pancreatic tumors expressing TM4SF5, and this effect was mediated, at least in part, by the production and suppressive function of the anti-TM4SF5 antibodies. Therefore, we suggest that targeting TM4SF5 could be a novel strategy to prevent or treat pancreatic cancer.
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Affiliation(s)
- Sangkyu Park
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea, .,Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea,
| | - Dongbum Kim
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea,
| | - Guang Wu
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea, .,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China,
| | - Harry Jung
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea,
| | - Jeong-A Park
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea, .,Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea,
| | - Hyung-Joo Kwon
- Center for Medical Science Research, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea, .,Department of Microbiology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
| | - Younghee Lee
- Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea, .,Biotechnology Research Institute, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea,
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32
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Neoptolemos JP, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer DH. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol 2018; 15:333-348. [PMID: 29717230 DOI: 10.1038/s41575-018-0005-x] [Citation(s) in RCA: 785] [Impact Index Per Article: 112.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.
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Affiliation(s)
- John P Neoptolemos
- Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
| | - Jörg Kleeff
- Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. .,Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
| | - Patrick Michl
- Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany
| | - Eithne Costello
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - William Greenhalf
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Daniel H Palmer
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
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33
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Dorjee P, Long ZW. A mixed treatment comparison of toxicity of gemcitabine combined with different targeted drugs in the treatment of advanced or metastatic pancreatic cancer. Cancer Biol Ther 2018; 19:497-506. [PMID: 29658816 DOI: 10.1080/15384047.2018.1433503] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The mixed treatment comparison study was performed in order to compare the toxicities of Gemcitabine and different targeted drug combinations in the treatment of advanced/metastatic pancreatic cancer (PC). Searches were performed from the inception of PubMed and Cochrane Library databases to February 2017. This study included randomized controlled trials (RCTs) of Gemcitabine and different targeted drug combinations in the treatment of advanced/metastatic PC. Odds ratio (OR) values were calculated by direct and indirect comparisons, and the surface under the cumulative ranking curves (SUCRA) were drawn. A total of six RCTs were finally incorporated into the study. These studies included six therapy regimens: Gemcitabine + Axitinib, Gemcitabine + Trametinib, Gemcitabine + Sorafenib, Gemcitabine + Bevacizumab, Gemcitabine + Erlotinib and Gemcitabine + Tipifarnib. The results showed that Gemcitabine + Axitinib combinations showed lower incidence rates of rashes (all grades) in comparison to Gemcitabine + Trametinib and Gemcitabine + Erlotinib combinations. Compared with Gemcitabine+ Trametinib combinations, Gemcitabine + Axitinib combinations showed lower incidence rates of diarrhea (grade ≥ 3). Moreover, the cluster analyses results revealed that Gemcitabine + Axitinib combinations and Gemcitabine + Sorafenib combinations showed lower incidence rates of hematotoxicity, while Gemcitabine + Axitinib combinations showed lower incidence rates of non-hematotoxicity. Collectively, the data provided strong evidence of Gemcitabine + Axitinib combinations showing lower incidence rates of non-hematotoxicity, and Gemcitabine + Axitinib and Gemcitabine + Sorafenib combinations may have lower incidence rates of hematotoxicity in the treatment of advanced/metastatic PC.
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Affiliation(s)
- Penpa Dorjee
- a Department of Medicine , Shigatse People's Hospital , Shigatse , P.R. China.,b Department of Gastric Cancer and Soft-Tissue Sarcoma Surgery , Fudan University Shanghai Cancer Center , Shanghai , P.R. China.,c Department of Oncology , Shanghai Medical College of Fudan University , Shanghai , P.R. China
| | - Zi-Wen Long
- a Department of Medicine , Shigatse People's Hospital , Shigatse , P.R. China.,b Department of Gastric Cancer and Soft-Tissue Sarcoma Surgery , Fudan University Shanghai Cancer Center , Shanghai , P.R. China.,c Department of Oncology , Shanghai Medical College of Fudan University , Shanghai , P.R. China
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34
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Perez M, Lucena-Cacace A, Marín-Gómez LM, Padillo-Ruiz J, Robles-Frias MJ, Saez C, Garcia-Carbonero R, Carnero A. Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src. Oncotarget 2018; 7:33111-24. [PMID: 27105527 PMCID: PMC5078079 DOI: 10.18632/oncotarget.8880] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 03/31/2016] [Indexed: 01/26/2023] Open
Abstract
Despite the development of new antineoplastic agents for the treatment of colorectal cancer (CRC), oxaliplatin and fluoropyrimidines remain the most commonly employed drugs for the treatment of both early and advanced disease. Intrinsic or acquired resistance is, however, an important limitation to pharmacological therapy, and the development of chemosensitization strategies constitute a major goal with important clinical implications. In the present work, we determined that high levels of activated Src kinase, measured as phospho-Src at the Tyr419 residue in CRC cell lines, can promote colorectal carcinoma cell resistance to oxaliplatin, but not to 5-fluorouracil (5FU), and that inhibition of this protein restores sensitivity to oxaliplatin. Similar results were observed with in vivo patient-derived xenograft (PDX) models that were orthotopically grown in murine livers. In PDX tumor lines derived from human CRC liver metastasis, dasatinib, a Src inhibitor, increases sensitivity to oxaliplatin only in tumors with high p-Src. However, dasatinib did not modify sensitivity to 5FU in any of the models. Our data suggest that chemoresistance induced by p-Src is specific to oxaliplatin, and that p-Src levels can be used to identify patients who may benefit from this combination therapy. These results are relevant for clinicians as they identify a novel biomarker of drug resistance that is suitable to pharmacological manipulation.
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Affiliation(s)
- Marco Perez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain
| | - Antonio Lucena-Cacace
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain
| | - Luis Miguel Marín-Gómez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.,Department of General Surgery, Virgen del Rocío University Hospital, Seville, Spain
| | - Javier Padillo-Ruiz
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.,Department of General Surgery, Virgen del Rocío University Hospital, Seville, Spain
| | - Maria Jose Robles-Frias
- Department of Pathology, Virgen del Rocío University Hospital, Seville, Spain.,Present address: HUVR-IBiS Biobank, Virgen del Rocío University Hospital, Seville, Spain
| | - Carmen Saez
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.,Department of Pathology, Virgen del Rocío University Hospital, Seville, Spain
| | - Rocio Garcia-Carbonero
- Department of Medical Oncology, Virgen del Rocío University Hospital, Seville, Spain.,Present address: Department of Medical Oncology, 12 of October University Hospital, Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain
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35
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Liang C, Shi S, Meng Q, Liang D, Ji S, Zhang B, Qin Y, Xu J, Ni Q, Yu X. Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going. Exp Mol Med 2017; 49:e406. [PMID: 29611542 PMCID: PMC5750480 DOI: 10.1038/emm.2017.255] [Citation(s) in RCA: 115] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 07/23/2017] [Accepted: 08/07/2017] [Indexed: 01/18/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.
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Affiliation(s)
- Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Dingkong Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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36
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Ruess DA, Görgülü K, Wörmann SM, Algül H. Pharmacotherapeutic Management of Pancreatic Ductal Adenocarcinoma: Current and Emerging Concepts. Drugs Aging 2017; 34:331-357. [PMID: 28349415 DOI: 10.1007/s40266-017-0453-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma is a devastating malignancy, which is the result of late diagnosis, aggressive disease, and a lack of effective treatment options. Thus, pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related death by 2030. This review summarizes recent developments of oncological therapy in the palliative setting of metastatic pancreatic ductal adenocarcinoma. It further compiles novel targets and therapeutic approaches as well as promising treatment combinations, which are presently in preclinical evaluation, covering several aspects of the hallmarks of cancer. Finally, challenges to the implementation of an individualized therapy approach in the context of precision medicine are discussed.
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Affiliation(s)
- Dietrich A Ruess
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
| | - Kivanc Görgülü
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Sonja M Wörmann
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
| | - Hana Algül
- Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.
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Abstract
Pancreatic cancer remains one of the most lethal cancers. These patients often have multiple symptoms, and integrated supportive care is critical in helping them remain well for as long as possible. Fluorouracil-based chemotherapy is known to improve overall survival (OS) by approximately 3 months, compared to the best supportive care alone. A 1997 study comparing gemcitabine and fluorouracil treatment of advanced pancreatic cancer patients showed an improvement in OS of 1 month in patients receiving gemcitabine. Over the next 10 years, multiple randomized studies compared single-agent gemcitabine with combination chemotherapy and showed no effective survival improvement. However, the addition of erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, was associated with a significant improvement in OS of approximately 2 weeks. However, adoption of this regimen has not been widespread because of its limited effect and added toxicity. Two clinical trials have recently prolonged OS in advanced pancreatic cancer patients by almost 1 year. The first compared FOLFIRINOX with gemcitabine alone, and was associated with a significant improvement in median survival. The second compared gemcitabine and nab-paclitaxel with gemcitabine alone, and was associated with improvements in OS. At present, these regimens are considered standard treatment for patients with good performance statuses.
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Affiliation(s)
- Hee Seung Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Seung Woo Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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38
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Adamska A, Domenichini A, Falasca M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int J Mol Sci 2017; 18:E1338. [PMID: 28640192 PMCID: PMC5535831 DOI: 10.3390/ijms18071338] [Citation(s) in RCA: 417] [Impact Index Per Article: 52.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 06/01/2017] [Accepted: 06/13/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), which constitutes 90% of pancreatic cancers, is the fourth leading cause of cancer-related deaths in the world. Due to the broad heterogeneity of genetic mutations and dense stromal environment, PDAC belongs to one of the most chemoresistant cancers. Most of the available treatments are palliative, with the objective of relieving disease-related symptoms and prolonging survival. Currently, available therapeutic options are surgery, radiation, chemotherapy, immunotherapy, and use of targeted drugs. However, thus far, therapies targeting cancer-associated molecular pathways have not given satisfactory results; this is due in part to the rapid upregulation of compensatory alternative pathways as well as dense desmoplastic reaction. In this review, we summarize currently available therapies and clinical trials, directed towards a plethora of pathways and components dysregulated during PDAC carcinogenesis. Emerging trends towards targeted therapies as the most promising approach will also be discussed.
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Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
| | - Alice Domenichini
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
| | - Marco Falasca
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
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Mattina J, Carlisle B, Hachem Y, Fergusson D, Kimmelman J. Inefficiencies and Patient Burdens in the Development of the Targeted Cancer Drug Sorafenib: A Systematic Review. PLoS Biol 2017; 15:e2000487. [PMID: 28158308 PMCID: PMC5291369 DOI: 10.1371/journal.pbio.2000487] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Accepted: 01/06/2017] [Indexed: 02/06/2023] Open
Abstract
Failure in cancer drug development exacts heavy burdens on patients and research systems. To investigate inefficiencies and burdens in targeted drug development in cancer, we conducted a systematic review of all prelicensure trials for the anticancer drug, sorafenib (Bayer/Onyx Pharmaceuticals). We searched Embase and MEDLINE databases on October 14, 2014, for prelicensure clinical trials testing sorafenib against cancers. We measured risk by serious adverse event rates, benefit by objective response rates and survival, and trial success by prespecified primary endpoint attainment with acceptable toxicity. The first two clinically useful applications of sorafenib were discovered in the first 2 efficacy trials, after five drug-related deaths (4.6% of 108 total) and 93 total patient-years of involvement (2.4% of 3,928 total). Thereafter, sorafenib was tested in 26 indications and 67 drug combinations, leading to one additional licensure. Drug developers tested 5 indications in over 5 trials each, comprising 56 drug-related deaths (51.8% of 108 total) and 1,155 patient-years (29.4% of 3,928 total) of burden in unsuccessful attempts to discover utility against these malignancies. Overall, 32 Phase II trials (26% of Phase II activity) were duplicative, lacked appropriate follow-up, or were uninformative because of accrual failure, constituting 1,773 patients (15.6% of 11,355 total) participating in prelicensure sorafenib trials. The clinical utility of sorafenib was established early in development, with low burden on patients and resources. However, these early successes were followed by rapid and exhaustive testing against various malignancies and combination regimens, leading to excess patient burden. Our evaluation of sorafenib development suggests many opportunities for reducing costs and unnecessary patient burden in cancer drug development.
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Affiliation(s)
- James Mattina
- Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, Quebec, Canada
| | - Benjamin Carlisle
- Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, Quebec, Canada
| | - Yasmina Hachem
- Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, Quebec, Canada
| | - Dean Fergusson
- Department of Clinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Jonathan Kimmelman
- Studies of Translation, Ethics and Medicine (STREAM), Biomedical Ethics Unit, McGill University, Montréal, Quebec, Canada
- * E-mail:
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40
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Lee HS, Chung MJ, Park JY, Bang S, Park SW, Kim HG, Noh MH, Lee SH, Kim YT, Kim HJ, Kim CD, Lee DK, Cho KB, Cho CM, Moon JH, Kim DU, Kang DH, Cheon YK, Choi HS, Kim TH, Kim JK, Moon J, Shin HJ, Song SY. A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea. Medicine (Baltimore) 2017; 96:e5702. [PMID: 28072706 PMCID: PMC5228666 DOI: 10.1097/md.0000000000005702] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 11/11/2016] [Accepted: 11/30/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND This phase III trial compared the efficacy and safety of gemcitabine plus capecitabine (GemCap) versus single-agent gemcitabine (Gem) in advanced pancreatic cancer as first-line chemotherapy. METHODS A total of 214 advanced pancreatic cancer patients were enrolled from 16 hospitals in South Korea between 2007 and 2011. Patients were randomly assigned to receive GemCap (oral capecitabine 1660 mg/m plus Gem 1000 mg/m by 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break every 4 weeks) or Gem (by 30-minute intravenous infusion weekly for 3 weeks every 4 weeks). RESULTS Median overall survival (OS) time, the primary end point, was 10.3 and 7.5 months in the GemCap and Gem arms, respectively (P = 0.06). Progression-free survival was 6.2 and 5.3 months in the GemCap and Gem arms, respectively (P = 0.08). GemCap significantly improved overall response rate compared with Gem alone (43.7% vs 17.6%; P = 0.001). Overall frequency of grade 3 or 4 toxicities was similar in each group. Neutropenia was the most frequent grade 3 or 4 toxicity in both groups. CONCLUSION GemCap failed to improve OS at a statistically significant level compared to Gem treatment. This study showed a trend toward improved OS compared to Gem alone. GemCap and Gem both exhibited similar safety profiles.
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Affiliation(s)
- Hee Seung Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul
| | - Moon Jae Chung
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul
| | - Jeong Youp Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul
| | - Seungmin Bang
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul
| | - Seung Woo Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul
| | - Ho Gak Kim
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu
| | - Myung Hwan Noh
- Department of Internal Medicine, Dong-A University College of Medicine, Busan
| | - Sang Hyub Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine
| | - Yong-Tae Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine
| | - Hyo Jung Kim
- Department of Internal Medicine, Korea University College of Medicine
| | - Chang Duck Kim
- Department of Internal Medicine, Korea University College of Medicine
| | - Dong Ki Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Kwang Bum Cho
- Department of Internal Medicine, Keimyung University School of Medicine
| | - Chang Min Cho
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu
| | - Jong Ho Moon
- Digestive Disease Center and Research Institute, Department of Internal Medicine, Soon Chun Hyang University School of Medicine, Bucheon and Seoul
| | - Dong Uk Kim
- Department of Internal Medicine, Pusan National University Hospital, Busan
| | - Dae Hwan Kang
- Departments of Internal Medicine, Pusan National University Hospital, Yangsan
| | - Young Koog Cheon
- Department of Internal Medicine, Digestive Disease Centre, Konkuk University School of Medicine, Seoul
| | - Ho Soon Choi
- Departments of Internal Medicine, Hanyang University College of Medicine, Seoul
| | - Tae Hyeon Kim
- Department of Internal Medicine, School of Medicine, Wonkwang University, Iksan
| | - Jae Kwang Kim
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, St. Mary's Hospital
| | - Jieun Moon
- Biostatistics Collaboration Unit, Medical Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Jung Shin
- Biostatistics Collaboration Unit, Medical Research Center, Yonsei University College of Medicine, Seoul, Korea
| | - Si Young Song
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul
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Lue HW, Cole B, Rao SAM, Podolak J, Van Gaest A, King C, Eide CA, Wilmot B, Xue C, Spellman PT, Heiser LM, Tyner JW, Thomas GV. Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma. Oncotarget 2016; 6:44675-87. [PMID: 26625308 PMCID: PMC4792584 DOI: 10.18632/oncotarget.5971] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2015] [Accepted: 10/04/2015] [Indexed: 12/25/2022] Open
Abstract
The intracytoplasmic tyrosine kinase Src serves both as a conduit and a regulator for multiple processes required for the proliferation and survival cancer cells. In some cancers, Src engages with receptor tyrosine kinases to mediate downstream signaling and in other cancers, it regulates gene expression. Src therefore represents a viable oncologic target. However, clinical responses to Src inhibitors, such as dasatinib have been disappointing to date. We identified Stat3 signaling as a potential bypass mechanism that enables renal cell carcinoma (RCC) cells to escape dasatinib treatment. Combined Src-Stat3 inhibition using dasatinib and CYT387 (a JAK/STAT inhibitor) synergistically reduced cell proliferation and increased apoptosis in RCC cells. Moreover, dasatinib and CYT387 combine to suppress YAP1, a transcriptional co-activator that promotes cell proliferation, survival and organ size. Importantly, this combination was well tolerated, and caused marked tumor inhibition in RCC xenografts. These results suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors.
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Affiliation(s)
- Hui-Wen Lue
- OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
| | - Brook Cole
- OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
| | - Soumya A M Rao
- OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
| | - Jennifer Podolak
- OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
| | - Ahna Van Gaest
- OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
| | - Carly King
- Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA
| | - Christopher A Eide
- Hematology and Oncology, Oregon Health and Science University, Portland, OR 97239, USA.,Howard Hughes Medical Institute, Oregon Health and Science University, Portland, OR 97239, USA
| | - Beth Wilmot
- Oregon Clinical and Translational Research Institute, Oregon Health and Science University, Portland, OR 97239, USA
| | - Changhui Xue
- OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA
| | - Paul T Spellman
- Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA
| | - Laura M Heiser
- Biomedical Engineering, Oregon Health and Science University, Portland, OR 97239, USA
| | - Jeffrey W Tyner
- Hematology and Oncology, Oregon Health and Science University, Portland, OR 97239, USA.,Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR 97239, USA
| | - George V Thomas
- OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA.,Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR 97239, USA
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Karanikas M, Esempidis A, Chasan ZTM, Deftereou T, Antonopoulou M, Bozali F, Amarantidis K, Man YG. Pancreatic Cancer from Molecular Pathways to Treatment Opinion. J Cancer 2016; 7:1328-39. [PMID: 27390608 PMCID: PMC4934041 DOI: 10.7150/jca.15419] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 05/01/2016] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer is considered one of the most lethal malignances. It has been observed that the five year survival rate is less than 5%. Early diagnosis, understanding the risk factors and investigation of the molecular pathways with targeted therapy are the keys for efficient treatment. Moreover; there are several local treatments for patients with unresectable pancreatic cancer. There are several combined therapies with chemotherapy and radiotherapy, however; a local therapy approach for many patients with poor performance status are in need. For those patients with good performance status new polychemotherapy regimens are used with success and increased survival improvement. Polychemotherapy has been observed to increase the rate of radical resections in some cases. Second line therapy is used for patients with good performance status and metastatic disease. Oxaliplatin-based regimens are mostly used, however; there are several other drugs that are being developed. Unfortunately, targeted therapy has not presented the expected efficiency. Moreover; immunotherapy; another treatment approach for several cancers types has again failed to present positive results for pancreatic cancer. In the current mini review, we will present information from the diagnosis to molecular pathways and targeted treatment.
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Affiliation(s)
- Michail Karanikas
- 1. 1ST Department of Surgery, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, Alexandroupolis, 68100 Thrace, Greece
| | - Agis Esempidis
- 1. 1ST Department of Surgery, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, Alexandroupolis, 68100 Thrace, Greece
| | - Zeinep Tzoutze Memet Chasan
- 1. 1ST Department of Surgery, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, Alexandroupolis, 68100 Thrace, Greece
| | - Theodora Deftereou
- 1. 1ST Department of Surgery, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, Alexandroupolis, 68100 Thrace, Greece
| | - Maria Antonopoulou
- 1. 1ST Department of Surgery, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, Alexandroupolis, 68100 Thrace, Greece
| | - Ferdi Bozali
- 1. 1ST Department of Surgery, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, Alexandroupolis, 68100 Thrace, Greece
| | - Kyriakos Amarantidis
- 2. Department of Medical Oncology, University Hospital of Alexandroupolis, Democritus University of Thrace, Dragana, Alexandroupolis, 68100 Thrace, Greece
| | - Yan-Gao Man
- 3. Research Laboratory and International Collaboration, Bon Secours Cancer Institute, VA, USA
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Kosmidis C, Sapalidis K, Kotidis E, Mixalopoulos N, Zarogoulidis P, Tsavlis D, Baka S, Man YG, Kanellos J. Pancreatic cancer from bench to bedside: molecular pathways and treatment options. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:165. [PMID: 27275478 PMCID: PMC4876273 DOI: 10.21037/atm.2016.05.11] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Accepted: 03/24/2016] [Indexed: 12/15/2022]
Abstract
In the last forty years the pancreatic cancer treatment has made advances, however; still novel drugs are needed. It is known that the five year survival rate remains around 5%. The best treatment option still remains surgery, if patients are diagnosed early. In the last decade the biology of pancreatic cancer has been vastly explored and novel agents such as; tyrosine kinase agents, or vaccines have been added as a treatment perspective. The big challenge is now to translate this knowledge in better outcomes for patients. In this current review we will present information from pancreatic cancer diagnosis to molecular pathways and treatment options; current and future.
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Di Marco M, Grassi E, Durante S, Vecchiarelli S, Palloni A, Macchini M, Casadei R, Ricci C, Panzacchi R, Santini D, Biasco G. State of the art biological therapies in pancreatic cancer. World J Gastrointest Oncol 2016; 8:55-66. [PMID: 26798437 PMCID: PMC4714146 DOI: 10.4251/wjgo.v8.i1.55] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 08/18/2015] [Accepted: 11/17/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with a five-year survival rate of approximately 5%. Several target agents have been tested in PDAC, but almost all have failed to demonstrate efficacy in late phase clinical trials, despite the better understanding of PDAC molecular biology generated by large cancer sequencing initiatives in the past decade. Eroltinib (a small-molecule tyrosine-kinase inhibitor of epidermal growth factor receptor) plus gemcitabine is the only schedule with a biological agent approved for advanced pancreatic cancer, but it has resulted in a very modest survival benefit in unselected patients. In our work, we report a summary of the main clinical trials (closed and ongoing) that refer to biological therapy evaluation in pancreatic cancer treatment.
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45
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Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma. Cancer Lett 2015; 381:201-10. [PMID: 26723874 DOI: 10.1016/j.canlet.2015.11.047] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 11/13/2015] [Accepted: 11/30/2015] [Indexed: 12/18/2022]
Abstract
The importance of angiogenesis in pancreatic ductal adenocarcinoma (PDAC) and its therapeutic potential have been explored in both pre-clinical and clinical studies. Human PDACs overexpress a number of angiogenic factors and their cognate high-affinity receptors, and anti-angiogenic agents reduce tumor volume, metastasis, and microvessel density (MVD), and improve survival in subcutaneous and orthotopic pre-clinical models. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful. This review will focus on these pre-clinical and clinical studies, the potential reasons for failure in the clinical setting, and ways these shortcomings could be addressed in future investigations of angiogenic mechanisms in PDAC.
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46
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Brunet LR, Hagemann T, Andrew G, Mudan S, Marabelle A. Have lessons from past failures brought us closer to the success of immunotherapy in metastatic pancreatic cancer? Oncoimmunology 2015; 5:e1112942. [PMID: 27141395 PMCID: PMC4839322 DOI: 10.1080/2162402x.2015.1112942] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 10/20/2015] [Accepted: 10/22/2015] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer is extremely resistant to chemo- and radiation-therapies due to its inherent genetic instability, the local immunosuppressive microenvironment and the remarkable desmoplastic stromal changes which characterize this cancer. Therefore, there is an urgent need for improvement on standard current therapeutic options. Immunotherapies aimed at harnessing endogenous antitumor immunity have shown promise in multiple tumor types. In this review, we give an overview of new immune-related therapeutic strategies currently being tested in clinical trials in pancreatic cancer. We propose that immunotherapeutic strategies in combination with current therapies may offer new hopes in this most deadly disease.
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Affiliation(s)
| | | | - Gayab Andrew
- Deparment of Clinical Oncology, Guy's and St Thomas' NHS Foundation Trust , London, UK
| | | | - Aurelien Marabelle
- INSERM, U1015, Villejuif, France; Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France; Drug Development Department, Gustave Roussy Cancer Campus, Villejuif, France
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Grapsa D, Saif MW, Syrigos K. Targeted therapies for pancreatic adenocarcinoma: Where do we stand, how far can we go? World J Gastrointest Oncol 2015; 7:172-177. [PMID: 26483872 PMCID: PMC4606172 DOI: 10.4251/wjgo.v7.i10.172] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/10/2015] [Accepted: 08/31/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic adenocarcinoma (usually referred to as pancreatic cancer) is a highly lethal and aggressive malignancy with a disease-related mortality almost equaling its incidence, and one of the most challenging cancers to treat. The notorious resistance of pancreatic cancer not only to conventional cytotoxic therapies but also to almost all targeted agents developed to date, continues to puzzle the oncological community and represents one of the biggest hurdles to reducing the death toll from this ominous disease. This editorial highlights the most important recent advances in preclinical and clinical research, with regards to targeted therapeutics for pancreatic cancer, outlines current challenges and provides an overview of potential future perspectives in this rapidly evolving field.
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Chiorean EG, Coveler AL. Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies. Drug Des Devel Ther 2015; 9:3529-45. [PMID: 26185420 PMCID: PMC4500614 DOI: 10.2147/dddt.s60328] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improving outcomes for metastatic cancer, refractory disease still poses significant challenges. Difficulties with early detection and the inherent chemo- and radio-resistant nature of this malignancy led to attempts to define the sequential biology of pancreatic cancer in order to improve survival outcomes. Pancreatic adenocarcinoma is characterized by several germline or acquired genetic mutations, the most common being KRAS (90%), CDK2NA (90%), TP53 (75%-90%), DPC4/SMAD4 (50%). In addition, the tumor microenvironment, chemoresistant cancer stem cells, and the desmoplastic stroma have been the target of some promising clinical investigations. Among the core pathways reproducibly shown to lead the development and progression of this disease, DNA repair, apoptosis, G1/S cell cycle transition, KRAS, Wnt, Notch, Hedgehog, TGF-beta, and other cell invasion pathways, have been the target of "precision therapeutics". No single molecularly targeted therapeutic though has been uniformly successful, probably due to the tumor heterogeneity, but biomarker research is evolving and it hopes to select more patients likely to benefit. Recent reports note activity with immunotherapies such as CD40 agonists, CCR2 inhibitors, cancer vaccines, and novel combinations against the immunosuppressive tumor milieu are ongoing. While many obstacles still exist, clearly we are making progress in deciphering the heterogeneity within pancreatic cancers. Integrating conventional and immunological targeting will be the key to effective treatment of this deadly disease.
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Affiliation(s)
| | - Andrew L Coveler
- Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA
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Poh AR, O'Donoghue RJ, Ernst M. Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells. Oncotarget 2015; 6:15752-71. [PMID: 26087188 PMCID: PMC4599235 DOI: 10.18632/oncotarget.4199] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 05/29/2015] [Indexed: 12/21/2022] Open
Abstract
The hematopoietic cell kinase (HCK) is a member of the SRC family of cytoplasmic tyrosine kinases (SFKs), and is expressed in cells of the myeloid and B-lymphocyte cell lineages. Excessive HCK activation is associated with several types of leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion proteins, and with functional interactions with receptor tyrosine kinases. Elevated HCK activity is also observed in many solid malignancies, including breast and colon cancer, and correlates with decreased patient survival rates. HCK enhances the secretion of growth factors and pro-inflammatory cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and tumor-promoting alternatively activated phenotype. Within tumor associated macrophages, HCK stimulates the formation of podosomes that facilitate extracellular matrix degradation, which enhance immune and epithelial cell invasion. By virtue of functional cooperation between HCK and bona fide oncogenic tyrosine kinases, excessive HCK activation can also reduce drug efficacy and contribute to chemo-resistance, while genetic ablation of HCK results in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK therefore provides an attractive therapeutic target to both, directly inhibit the growth of cancer cells, and indirectly curb the source of tumor-promoting changes in the tumor microenvironment.
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Affiliation(s)
- Ashleigh R. Poh
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Victoria, Australia
| | - Robert J.J. O'Donoghue
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Victoria, Australia
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Victoria, Australia
| | - Matthias Ernst
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Victoria, Australia
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Victoria, Australia
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50
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Kim EJ, Semrad TJ, Bold RJ. Phase II clinical trials on investigational drugs for the treatment of pancreatic cancers. Expert Opin Investig Drugs 2015; 24:781-94. [PMID: 25809274 PMCID: PMC4684166 DOI: 10.1517/13543784.2015.1026963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Despite some recent advances in treatment options, pancreatic cancer remains a devastating disease with poor outcomes. In a trend contrary to most malignancies, both incidence and mortality continue to rise due to pancreatic cancer. The majority of patients present with advanced disease and there are no treatment options for this stage that have demonstrated a median survival > 1 year. As the penultimate step prior to Phase III studies involving hundreds of patients, Phase II clinical trials provide an early opportunity to evaluate the efficacy of new treatments that are desperately needed for this disease. AREAS COVERED This review covers the results of published Phase II clinical trials in advanced pancreatic adenocarcinoma published within the past 5 years. The treatment results are framed in the context of the current standards of care and the historic challenge of predicting Phase III success from Phase II trial results. EXPERT OPINION Promising therapies remain elusive in pancreatic cancer based on recent Phase II clinical trial results. Optimization and standardization of clinical trial design in the Phase II setting, with consistent incorporation of biomarkers, is needed to more accurately identify promising therapies that warrant Phase III evaluation.
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Affiliation(s)
- Edward J. Kim
- Division of Hematology and Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA
| | - Thomas J. Semrad
- Division of Hematology and Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA
| | - Richard J. Bold
- Division of Surgical Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA
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