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Watters CR, Barro O, Gabere M, Masuda MY, Elliott NM, Raupach EA, Ferdous KU, Tesfay MZ, Moaven O, Zhou Y, Barrett MT, Buetow KH, Nagalo BM, Borad MJ. Resistance signatures to oncolytic vesiculoviruses in pancreatic ductal adenocarcinoma. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200937. [PMID: 40123977 PMCID: PMC11930419 DOI: 10.1016/j.omton.2025.200937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 11/29/2024] [Accepted: 01/14/2025] [Indexed: 03/25/2025]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) shows limited response to conventional therapies and immunotherapy due to dense stromal barriers and poor immunogenicity. Oncolytic vesiculoviruses hold therapeutic potential for PDAC by lysis of PDAC cells to release tumor-associated antigens, increasing tumor immunogenicity. We previously reported the efficacy of a chimeric vesicular stomatitis virus (VSV) expressing Morreton virus (MorV) glycoprotein in sarcoma. Here, we evaluated the oncolytic potency of MorV and chimeric virus, VMG, in PDAC models. VMG exhibited heterogeneous oncolysis across human PDAC cell lines and PDX cells, similar to parental viruses VSV and MorV. To evaluate potential signatures correlated with resistance to oncolytic vesiculoviruses, we compared transcriptomes of cell lines characterized as sensitive or resistant to oncolysis in vitro. We identified epithelial development and biological adhesion gene sets were significantly associated with vesiculovirus resistance. Additionally, escaped PDAC cells surviving two cycles of infection with VSV showed significant upregulation of stress keratins and downregulation of genes involved in retinoic acid metabolism and cell cycle. An overlapping 39 genes were higher in resistant cell lines at baseline as well as upregulated in escaped PDAC cells. Several resistance-associated genes are targets of anti-cancer therapies in development, offering potential combination approaches with oncolytic vesiculoviruses.
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Affiliation(s)
- Chelsae R. Watters
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Oumar Barro
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Musa Gabere
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Mia Y. Masuda
- Department of Immunology, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Natalie M. Elliott
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Elizabeth A. Raupach
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Khandoker Usran Ferdous
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR 72205, USA
| | - Mulu Z. Tesfay
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR 72205, USA
| | - Omeed Moaven
- Division of Surgical Oncology, Department of Surgery, Louisiana State University (LSU) Health, New Orleans, LA 70112, USA
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, LSU Health, New Orleans, LA 70112, USA
| | - Yumei Zhou
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Michael T. Barrett
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ 85054, USA
| | - Kenneth H. Buetow
- Computational Sciences and Informatics Program for Complex Adaptive System, Arizona State University, Tempe, AZ 85281, USA
| | - Bolni Marius Nagalo
- Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- The Winthrop P. Rockefeller Cancer Institute, UAMS, Little Rock, AR 72205, USA
| | - Mitesh J. Borad
- Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ 85259, USA
- Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Mayo Clinic Cancer Center, Mayo Clinic, Phoenix, AZ 85054, USA
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Hao T, Li Y, Ren Q, Zeng Y, Gao L, Zhu W, Liang J, Lin Y, Hu J, Yan G, Sun S, Cai J. circ-1584 selectively promotes the antitumor activity of the oncolytic virus M1 on pancreatic cancer. MOLECULAR THERAPY. ONCOLOGY 2025; 33:200919. [PMID: 39866243 PMCID: PMC11760297 DOI: 10.1016/j.omton.2024.200919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/25/2024] [Accepted: 12/13/2024] [Indexed: 01/28/2025]
Abstract
Pancreatic cancer is among the most challenging tumors to treat, and due to its immune tolerance characteristics, existing immunotherapy methods are not effective in alleviating the disease. Oncolytic virus therapy, a potential new strategy for treating pancreatic cancer, also faces the limitation of being ineffective when used alone. Elucidating the key host endogenous circular RNAs (circRNAs) involved in M1 virus-mediated killing of pancreatic ductal adenocarcinoma (PDAC) cells may help overcome this limitation. Here, we report that the oncolytic virus M1, a nonpathogenic alphavirus, exhibits different cell viability-inhibitory effects on different pancreatic cancer cells in the clinical stage. Through high-throughput circRNA sequencing, we found that circRNA expression varies among these cells. Further gain-of-function and loss-of-function experiments have shown that circ-1584 can selectively enhance the anti-pancreatic cancer effects of the M1 virus in vitro and in vivo. Additionally, circ-1584 may negatively regulate miR-578 to modulate the anti-pancreatic cancer effects of the M1 virus. Our findings lay the foundation for using circRNA as an adjuvant to enhance the M1 virus efficacy against pancreatic cancer.
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Affiliation(s)
- Taofang Hao
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuanyuan Li
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qianyao Ren
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ying Zeng
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Leyi Gao
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Wenbo Zhu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jiankai Liang
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuan Lin
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Advanced Medical Technology Center, The First Affiliated Hospital-Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Human Microbiome and Elderly Chronic Diseases, Ministry of Education, Beijing, China
| | - Jun Hu
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guangmei Yan
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shuxin Sun
- Pancreatic Center, Guangdong Provincial People’s Hospital, Guangzhou, China
| | - Jing Cai
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Molecular Biology and Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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3
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Metrangolo V, Blomquist MH, Dutta A, Gårdsvoll H, Krigslund O, Nørregaard KS, Jürgensen HJ, Ploug M, Flick MJ, Behrendt N, Engelholm LH. Targeting uPAR with an antibody-drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models. SCIENCE ADVANCES 2025; 11:eadq0513. [PMID: 39823326 PMCID: PMC11740940 DOI: 10.1126/sciadv.adq0513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 12/17/2024] [Indexed: 01/19/2025]
Abstract
Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored the urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression in this stroma-dense tumor. We generated a site-specific ADC offering high-affinity, cross-species reactivity, and efficient internalization of the anti-uPAR monoclonal antibody, FL1, carrying a potent anthracycline derivative (PNU-158692). In vitro, FL1-PNU exhibited potent and specific cytotoxicity against uPAR-expressing PDAC cell lines, stromal and immune cells, and bystander killing of uPAR-negative cells. In vivo, the ADC induced remission or sustained tumor regression and extended survival in xenograft models. In syngeneic orthotopic models, the antitumor effect promoted immunomodulation by enhancing infiltrating immune effectors and decreasing immunosuppressive cells. This study lays grounds for further exploring FL1-PNU as a putative clinical ADC candidate, potentially providing a promising therapeutic avenue for PDAC as a monotherapy or in combinatorial regimens.
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Affiliation(s)
- Virginia Metrangolo
- The Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen, Denmark
- Biotech Research & Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | | | - Ananya Dutta
- Department of Medicine, Duke University, Durham, NC 27710, USA
| | - Henrik Gårdsvoll
- The Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen, Denmark
| | - Oliver Krigslund
- The Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen, Denmark
| | | | | | - Michael Ploug
- The Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen, Denmark
- Biotech Research & Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Matthew J. Flick
- Department of Medicine and the UNC Blood Research Center, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Niels Behrendt
- The Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen, Denmark
- Biotech Research & Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, GK-2200 Copenhagen, Denmark
| | - Lars H. Engelholm
- The Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen, Denmark
- Biotech Research & Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
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Song W, Hu H, Yuan Z, Yao H. A prognostic model for anoikis-related genes in pancreatic cancer. Sci Rep 2024; 14:15200. [PMID: 38956290 PMCID: PMC11220081 DOI: 10.1038/s41598-024-65981-7] [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: 04/18/2024] [Accepted: 06/26/2024] [Indexed: 07/04/2024] Open
Abstract
Anoikis, a distinct form of programmed cell death, is crucial for both organismal development and maintaining tissue equilibrium. Its role extends to the proliferation and progression of cancer cells. This study aimed to establish an anoikis-related prognostic model to predict the prognosis of pancreatic cancer (PC) patients. Gene expression data and patient clinical profiles were sourced from The Cancer Genome Atlas (TCGA-PAAD: Pancreatic Adenocarcinoma) and the International Cancer Genome Consortium (ICGC-PACA: Pancreatic Ductal Adenocarcinoma). Non-cancerous pancreatic tissue gene expression data were obtained from the Genotype-Tissue Expression (GTEx) project. The R package was used to construct anoikis-related PC prognostic models, which were later validated with the ICGC-PACA database. Survival analyses demonstrated a poorer prognosis for patients in the high-risk group, consistent across both TCGA-PAAD and ICGC-PACA datasets. A nomogram was designed as a predictive tool to estimate patient mortality. The study also analyzed tumor mutations and immune infiltration across various risk groups, uncovering notable differences in tumor mutation patterns and immune landscapes between high- and low-risk groups. In conclusion, this research successfully developed a prognostic model centered on anoikis-related genes, offering a novel tool for predicting the clinical trajectory of PC patients.
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Affiliation(s)
- Wenbin Song
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, People's Republic of China
- Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin, 300052, People's Republic of China
| | - Haiyang Hu
- Department of Cardiac Critical Care Medicine, Affiliated Hospital of Jining Medical University, Jining, 272007, People's Republic of China
| | - Zhengbo Yuan
- School of Medicine, Xiamen University, No.4221 Xiangan South Road, Xiangan District, Xiamen, 361102, People's Republic of China.
- Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No.55 Zhenghai load, Siming District, Xiamen, 361001, People's Republic of China.
| | - Hao Yao
- Department of Hepatological Surgery, The Second Hospital of Tianjin Medical University, No.23 Pingjiang Road, Hexi District, Tianjin, 300211, People's Republic of China.
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5
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Silva LGDO, Lemos FFB, Luz MS, Rocha Pinheiro SL, Calmon MDS, Correa Santos GL, Rocha GR, de Melo FF. New avenues for the treatment of immunotherapy-resistant pancreatic cancer. World J Gastrointest Oncol 2024; 16:1134-1153. [PMID: 38660642 PMCID: PMC11037047 DOI: 10.4251/wjgo.v16.i4.1134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 01/26/2024] [Accepted: 03/04/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer (PC) is characterized by its extremely aggressive nature and ranks 14th in the number of new cancer cases worldwide. However, due to its complexity, it ranks 7th in the list of the most lethal cancers worldwide. The pathogenesis of PC involves several complex processes, including familial genetic factors associated with risk factors such as obesity, diabetes mellitus, chronic pancreatitis, and smoking. Mutations in genes such as KRAS, TP53, and SMAD4 are linked to the appearance of malignant cells that generate pancreatic lesions and, consequently, cancer. In this context, some therapies are used for PC, one of which is immunotherapy, which is extremely promising in various other types of cancer but has shown little response in the treatment of PC due to various resistance mechanisms that contribute to a drop in immunotherapy efficiency. It is therefore clear that the tumor microenvironment (TME) has a huge impact on the resistance process, since cellular and non-cellular elements create an immunosuppressive environment, characterized by a dense desmoplastic stroma with cancer-associated fibroblasts, pancreatic stellate cells, extracellular matrix, and immunosuppressive cells. Linked to this are genetic mutations in TP53 and immunosuppressive factors that act on T cells, resulting in a shortage of CD8+ T cells and limited expression of activation markers such as interferon-gamma. In this way, finding new strategies that make it possible to manipulate resistance mechanisms is necessary. Thus, techniques such as the use of TME modulators that block receptors and stromal molecules that generate resistance, the use of genetic manipulation in specific regions, such as microRNAs, the modulation of extrinsic and intrinsic factors associated with T cells, and, above all, therapeutic models that combine these modulation techniques constitute the promising future of PC therapy. Thus, this study aims to elucidate the main mechanisms of resistance to immunotherapy in PC and new ways of manipulating this process, resulting in a more efficient therapy for cancer patients and, consequently, a reduction in the lethality of this aggressive cancer.
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Affiliation(s)
| | - Fabian Fellipe Bueno Lemos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Marcel Silva Luz
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Samuel Luca Rocha Pinheiro
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Mariana dos Santos Calmon
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Lima Correa Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Gabriel Reis Rocha
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Lekan AA, Weiner LM. The Role of Chemokines in Orchestrating the Immune Response to Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:559. [PMID: 38339310 PMCID: PMC10854906 DOI: 10.3390/cancers16030559] [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: 01/08/2024] [Revised: 01/24/2024] [Accepted: 01/26/2024] [Indexed: 02/12/2024] Open
Abstract
Chemokines are small molecules that function as chemotactic factors which regulate the migration, infiltration, and accumulation of immune cells. Here, we comprehensively assess the structural and functional role of chemokines, examine the effects of chemokines that are present in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME), specifically those produced by cancer cells and stromal components, and evaluate their impact on immune cell trafficking, both in promoting and suppressing anti-tumor responses. We further explore the impact of chemokines on patient outcomes in PDAC and their role in the context of immunotherapy treatments, and review clinical trials that have targeted chemokine receptors and ligands in the treatment of PDAC. Lastly, we highlight potential strategies that can be utilized to harness chemokines in order to increase cytotoxic immune cell infiltration and the anti-tumor effects of immunotherapy.
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Affiliation(s)
| | - Louis M. Weiner
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20057, USA;
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Dabiri R, Rashid MU, Khan OS, Jehanzeb S, Alomari M, Zafar H, Zahid E, Rahman AU, Karam A, Ahmad S. Immune modulators for pancreatic ductal adenocarcinoma therapy. IMMUNE LANDSCAPE OF PANCREATIC CANCER DEVELOPMENT AND DRUG RESISTANCE 2024:103-129. [DOI: 10.1016/b978-0-443-23523-8.00021-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Zhang N, Guan Y, Li J, Yu J, Yi T. Inactivation of the DNA-sensing pathway facilitates oncolytic herpes simplex virus inhibition of pancreatic ductal adenocarcinoma growth. Int Immunopharmacol 2023; 124:110969. [PMID: 37774484 DOI: 10.1016/j.intimp.2023.110969] [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: 06/29/2023] [Revised: 09/10/2023] [Accepted: 09/18/2023] [Indexed: 10/01/2023]
Abstract
Oncolytic viruses are a new class of therapeutic agents for the treatment of cancer that have shown promising results in clinical trials. Oncolytic virus-mediated tumor rejection is highly dependent on viral replication in tumor cells to induce cell death. However, the antiviral immune response of tumor cells limits the replication capacity of oncolytic viruses. We hypothesized that inhibition of the antiviral immune response in infected cells would enhance the antitumor effect. Here, we confirmed that ablation of the key adaptor protein of cellular immunity, STING, significantly suppressed the antiviral immune response and promoted oncolytic herpes simplex virus-1 (oHSV1) proliferation in tumor cells. In a murine pancreatic ductal adenocarcinoma (PDAC) model, oHSV1 enhanced tumor suppression and prolonged the survival of mice in the absence of STING. On this basis, we further found that the TBK1 inhibitor can also significantly enhance the tumor-control ability of oHSV1. Our studies provide a novel strategy for oncolytic virus therapy by inhibiting the intrinsic antiviral response in solid tumors to improve antitumor efficacy.
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Affiliation(s)
- Nianchao Zhang
- Key Laboratory of Microbial Functional Genomics of the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Yude Guan
- Key Laboratory of Microbial Functional Genomics of the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Jie Li
- Key Laboratory of Microbial Functional Genomics of the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Jingxuan Yu
- Key Laboratory of Microbial Functional Genomics of the Ministry of Education, College of Life Sciences, Nankai University, Tianjin, China
| | - Tailong Yi
- Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
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Laface C, Memeo R, Maselli FM, Santoro AN, Iaia ML, Ambrogio F, Laterza M, Cazzato G, Guarini C, De Santis P, Perrone M, Fedele P. Immunotherapy and Pancreatic Cancer: A Lost Challenge? Life (Basel) 2023; 13:1482. [PMID: 37511856 PMCID: PMC10381818 DOI: 10.3390/life13071482] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 06/22/2023] [Accepted: 06/29/2023] [Indexed: 07/30/2023] Open
Abstract
Although immunotherapy has proved to be a very efficient therapeutic strategy for many types of tumors, the results for pancreatic cancer (PC) have been very poor. Indeed, chemotherapy remains the standard treatment for this tumor in the advanced stage. Clinical data showed that only a small portion of PC patients with high microsatellite instability/mismatch repair deficiency benefit from immunotherapy. However, the low prevalence of these alterations was not sufficient to lead to a practice change in the treatment strategy of this tumor. The main reasons for the poor efficacy of immunotherapy probably lie in the peculiar features of the pancreatic tumor microenvironment in comparison with other malignancies. In addition, the biomarkers usually evaluated to define immunotherapy efficacy in other cancers appear to be useless in PC. This review aims to describe the main features of the pancreatic tumor microenvironment from an immunological point of view and to summarize the current data on immunotherapy efficacy and immune biomarkers in PC.
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Affiliation(s)
- Carmelo Laface
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” General Regional Hospital, 70021 Acquaviva Delle Fonti, Italy
| | | | | | - Maria Laura Iaia
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Francesca Ambrogio
- Section of Dermatology, Department of Biomedical Science and Human Oncology, University of Bari, 70124 Bari, Italy
| | - Marigia Laterza
- Division of Cardiac Surgery, University of Bari, 70124 Bari, Italy
| | - Gerardo Cazzato
- Department of Emergency and Organ Transplantation, Pathology Section, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy
| | - Chiara Guarini
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Pierluigi De Santis
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Martina Perrone
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
| | - Palma Fedele
- Medical Oncology, Dario Camberlingo Hospital, 72021 Francavilla Fontana, Italy
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10
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Gryciuk A, Rogalska M, Baran J, Kuryk L, Staniszewska M. Oncolytic Adenoviruses Armed with Co-Stimulatory Molecules for Cancer Treatment. Cancers (Basel) 2023; 15:cancers15071947. [PMID: 37046608 PMCID: PMC10093006 DOI: 10.3390/cancers15071947] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/19/2023] [Accepted: 03/22/2023] [Indexed: 04/14/2023] Open
Abstract
In clinical trials, adenovirus vectors (AdVs) are commonly used platforms for human gene delivery therapy. High genome capacity and flexibility in gene organization make HAdVs suitable for cloning. Recent advancements in molecular techniques have influenced the development of genetically engineered adenovirus vectors showing therapeutic potential. Increased molecular understanding of the benefits and limitations of HAdVs in preclinical research and clinical studies is a crucial point in the engineering of refined oncolytic vectors. This review presents HAdV species (A-G) used in oncotherapy. We describe the adenovirus genome organizations and modifications, the possibilities oncolytic viruses offer, and their current limitations. Ongoing and ended clinical trials based on oncolytic adenoviruses are presented. This review provides a broad overview of the current knowledge of oncolytic therapy. HAdV-based strategies targeting tumors by employing variable immune modifiers or delivering immune stimulatory factors are of great promise in the field of immune oncologyy This approach can change the face of the fight against cancer, supplying the medical tools to defeat tumors more selectively and safely.
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Affiliation(s)
- Aleksander Gryciuk
- Department of Microbiology, Molecular Genetics and Genomics, Centre of Advanced Materials and Technology CEZAMAT, Warsaw University of Technology, 02-822 Warsaw, Poland
| | - Marta Rogalska
- Department of Microbiology, Molecular Genetics and Genomics, Centre of Advanced Materials and Technology CEZAMAT, Warsaw University of Technology, 02-822 Warsaw, Poland
| | - Joanna Baran
- Department of Microbiology, Molecular Genetics and Genomics, Centre of Advanced Materials and Technology CEZAMAT, Warsaw University of Technology, 02-822 Warsaw, Poland
| | - Lukasz Kuryk
- Department of Virology, National Institute of Public Health NIH-NRI, 00-791 Warsaw, Poland
- Valo Therapeutics, 00790 Helsinki, Finland
| | - Monika Staniszewska
- Department of Microbiology, Molecular Genetics and Genomics, Centre of Advanced Materials and Technology CEZAMAT, Warsaw University of Technology, 02-822 Warsaw, Poland
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11
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Maqsood Q, Sumrin A, Iqbal M, Hussain N, Mahnoor M, Zafar Saleem M, Perveen R. A Winning New Combination? Toward Clinical Application in Oncology. Cancer Control 2023; 30:10732748231175240. [PMID: 37166227 PMCID: PMC10184224 DOI: 10.1177/10732748231175240] [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: 12/01/2022] [Revised: 03/04/2023] [Accepted: 04/17/2023] [Indexed: 05/12/2023] Open
Abstract
Immunotherapy has substantial attention in oncology due to the success of CTLA-4 and PD-1 inhibitors in the treatment of melanoma, lung cancer, head and neck cancer, renal cell carcinoma, and Hodgkin's lymphoma. A deeper understanding of interaction of tumor with its environment and the immune system provides best guide for oncology research. Recent studies in oncology have explained how a tumor alters antigen presentation, avoids detection, and activation of the host immune system to live and develop. Understanding the connections between the tumor and the immune system has resulted in several innovative therapy options. The extensive field of gene therapy has provided a number of cutting-edge medicines that are expected to play an important role in lowering cancer-related mortality. This article explains the history, important breakthroughs, and future prospects for three separate gene therapy treatment modalities: immunotherapy, oncolytic virotherapy, and gene transfer. Immunotherapies have completely changed how cancer is treated, especially for individuals whose condition was previously thought to be incurable. Examples include ACT (adoptive cell therapy) and ICB (immune checkpoint blockade). This review article will discuss the relationship between the immune response to cancer and the mechanisms of immunotherapy resistance. It will cover combination drugs authorized by the US Food and Drug Administration and provide a thorough overview of how these drugs are doing clinically right now. Cytokines, vaccines, and other soluble immunoregulatory agents, innate immune modifiers, ACT, virotherapy, and other treatment modalities will all be covered in detail.
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Affiliation(s)
- Quratulain Maqsood
- Centre for Applied Molecular Biology, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan
| | - Aleena Sumrin
- Centre for Applied Molecular Biology, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan
| | - Maryam Iqbal
- Centre for Applied Molecular Biology, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan
| | - Nazim Hussain
- Centre for Applied Molecular Biology, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan
| | - Muhammada Mahnoor
- Department of Rehabilitation Sciences, Akhtar Saeed Medical & Dental College, Lahore, Pakistan
| | - Muhammad Zafar Saleem
- Centre for Applied Molecular Biology, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan
| | - Rukhsana Perveen
- Centre for Applied Molecular Biology, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan
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12
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Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer. Cancer Immunol Immunother 2022; 72:1285-1300. [PMID: 36436021 DOI: 10.1007/s00262-022-03334-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 11/18/2022] [Indexed: 11/28/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.
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13
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Di Federico A, Mosca M, Pagani R, Carloni R, Frega G, De Giglio A, Rizzo A, Ricci D, Tavolari S, Di Marco M, Palloni A, Brandi G. Immunotherapy in Pancreatic Cancer: Why Do We Keep Failing? A Focus on Tumor Immune Microenvironment, Predictive Biomarkers and Treatment Outcomes. Cancers (Basel) 2022; 14:cancers14102429. [PMID: 35626033 PMCID: PMC9139656 DOI: 10.3390/cancers14102429] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/06/2022] [Accepted: 05/11/2022] [Indexed: 12/20/2022] Open
Abstract
Simple Summary In pancreatic cancer, immunotherapy and targeted therapies have not brought about the therapeutic revolution that has been observed in other malignancies. Among the reasons to explain this difference is the possibly crucial role played by the pancreatic tumor microenvironment, which has unique features and is different from that of other neoplasms. The aim of this review is to provide a comprehensive overview of the distinctive tumor immune microenvironment of pancreatic cancer and to summarize existing data about the use of immunotherapy and immune biomarkers in this cancer. Abstract The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC.
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Affiliation(s)
- Alessandro Di Federico
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
- Correspondence:
| | - Mirta Mosca
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Rachele Pagani
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Riccardo Carloni
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Giorgio Frega
- Osteoncology, Bone and Soft Tissue Sarcomas, and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy;
| | - Andrea De Giglio
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico “Don Tonino Bello”, I.R.C.C.S. Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco 65, 70124 Bari, Italy;
| | - Dalia Ricci
- Departmental Unit of Medical Oncology, ASL BA, 20142 Milan, Italy;
| | - Simona Tavolari
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Mariacristina Di Marco
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Andrea Palloni
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
| | - Giovanni Brandi
- Division of Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Albertoni, 15, 40138 Bologna, Italy; (M.M.); (R.P.); (R.C.); (A.D.G.); (M.D.M.); (A.P.); (G.B.)
- Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Via Giuseppe Massarenti, 9, 40138 Bologna, Italy;
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14
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Tonini V, Zanni M. Pancreatic cancer in 2021: What you need to know to win. World J Gastroenterol 2021; 27:5851-5889. [PMID: 34629806 PMCID: PMC8475010 DOI: 10.3748/wjg.v27.i35.5851] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/14/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the solid tumors with the worst prognosis. Five-year survival rate is less than 10%. Surgical resection is the only potentially curative treatment, but the tumor is often diagnosed at an advanced stage of the disease and surgery could be performed in a very limited number of patients. Moreover, surgery is still associated with high post-operative morbidity, while other therapies still offer very disappointing results. This article reviews every aspect of pancreatic cancer, focusing on the elements that can improve prognosis. It was written with the aim of describing everything you need to know in 2021 in order to face this difficult challenge.
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Affiliation(s)
- Valeria Tonini
- Department of Medical Sciences and Surgery, University of Bologna- Emergency Surgery Unit, IRCCS Sant’Orsola Hospital, Bologna 40121, Italy
| | - Manuel Zanni
- University of Bologna, Emergency Surgery Unit, IRCCS Sant'Orsola Hospital, Bologna 40121, Italy
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15
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Islam S, Espitia CM, Persky DO, Carew JS, Nawrocki ST. Targeting JAK/STAT Signaling Antagonizes Resistance to Oncolytic Reovirus Therapy Driven by Prior Infection with HTLV-1 in Models of T-Cell Lymphoma. Viruses 2021; 13:1406. [PMID: 34372612 PMCID: PMC8310324 DOI: 10.3390/v13071406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 07/11/2021] [Accepted: 07/14/2021] [Indexed: 12/12/2022] Open
Abstract
Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains challenging and new treatment options are urgently needed. With the goal of developing a novel therapeutic approach for TCL, we investigated the activity of the clinical formulation of oncolytic reovirus (Reolysin, Pelareorep) in TCL models. Our studies revealed that HTLV-1-negative TCL cells were highly sensitive to Reolysin-induced cell death, but HTLV-1-positive TCL cells were resistant. Consistent with these data, reovirus displayed significant viral accumulation in HTLV-1-negative cells, but failed to efficiently replicate in HTLV-1-positive cells. Transcriptome analyses of HTLV-1-positive vs. negative cells revealed a significant increase in genes associated with retroviral infection including interleukin-13 and signal transducer and activator of transcription 5 (STAT5). To investigate the relationship between HTLV-1 status and sensitivity to Reolysin, we infected HTLV-1-negative cells with HTLV-1. The presence of HTLV-1 resulted in significantly decreased sensitivity to Reolysin. Treatment with the JAK inhibitor ruxolitinib suppressed STAT5 phosphorylation and expression of the key anti-viral response protein MX1 and enhanced the anti-TCL activity of Reolysin in both HTLV-1-positive and negative cells. Our data demonstrate that the inhibition of the JAK/STAT pathway can be used as a novel approach to antagonize the resistance of HTLV-1-positive cells to oncolytic virus therapy.
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Affiliation(s)
- Shariful Islam
- Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, USA; (S.I.); (C.M.E.); (J.S.C.)
| | - Claudia M. Espitia
- Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, USA; (S.I.); (C.M.E.); (J.S.C.)
| | - Daniel O. Persky
- Division of Hematology and Oncology, Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, USA;
| | - Jennifer S. Carew
- Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, USA; (S.I.); (C.M.E.); (J.S.C.)
| | - Steffan T. Nawrocki
- Division of Translational and Regenerative Medicine, Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, USA; (S.I.); (C.M.E.); (J.S.C.)
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16
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Galanopoulos M, Doukatas A, Gkeros F, Viazis N, Liatsos C. Room for improvement in the treatment of pancreatic cancer: Novel opportunities from gene targeted therapy. World J Gastroenterol 2021; 27:3568-3580. [PMID: 34239270 PMCID: PMC8240062 DOI: 10.3748/wjg.v27.i24.3568] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/11/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the highest and in fact, unchanged mortality-associated tumor, with an exceptionally low survival rate due to its challenging diagnostic approach. So far, its treatment is based on a combination of approaches (such as surgical resection with or rarely without chemotherapeutic agents), but with finite limits. Thus, looking for additional space to improve pancreatic tumorigenesis therapeutic approach, research has focused on gene therapy with unexpectedly growing horizons not only for the treatment of inoperable pancreatic disease, but also for its early stages. In vivo gene delivery viral vectors, despite few disadvantages (possible immunogenicity, toxicity, mutagenicity, or high cost), could be one of the most efficient cancer gene therapeutic strategies for clinical application due to their superiority compared with other systems (ex vivo delivery strategies). Their dominance consists of simple preparation, easy operation and a wide range of functions. Adenoviruses are one of the most common used vectors, inducing strong immune as well as inflammatory reactions. Oncolytic virotherapy, using the above mentioned in vivo viral vectors, is one of the most promising non-pathogenic, highly-selective cytotoxic anti-cancer therapy using anti-cancer agents with high anti-tumor potency and strong oncolytic effect. There have been a variety of targeted therapeutic and pre-clinical strategies tested for gene therapy in pancreatic cancer such as gene-editing systems (e.g., clustered regularly interspaced palindromic repeats-Cas9), RNA interference technology (e.g., microRNAs, short hairpin RNA or small interfering RNA), adoptive immunotherapy and vaccination (e.g., chimeric antigen receptor T-cell therapy) with encouraging results.
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Affiliation(s)
- Michail Galanopoulos
- Department of Gastroenterology, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Aris Doukatas
- Department of Pharmacy, National and Kapodistrian University of Athens, Athens GR 15772, Greece
| | - Filippos Gkeros
- Department of Gastroenterology, Evangelismos, Ophthalmiatreion Athinon and Polyclinic Hospitals, Athens 10676, Greece
| | - Nikos Viazis
- Department of Gastroenterology, Evangelismos, Ophthalmiatreion Athinon and Polyclinic Hospitals, Athens 10676, Greece
| | - Christos Liatsos
- Department of Gastroenterology, 401 General Military Hospital, Athens 11525, Greece
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17
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Zhang Y, Zhang T, Yang W, Chen H, Geng X, Li G, Chen H, Wang Y, Li L, Sun B. Beneficial Diets and Pancreatic Cancer: Molecular Mechanisms and Clinical Practice. Front Oncol 2021; 11:630972. [PMID: 34123787 PMCID: PMC8193730 DOI: 10.3389/fonc.2021.630972] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/19/2021] [Indexed: 01/02/2023] Open
Abstract
Pancreatic cancer (PC) is a malignant tumor with high invasiveness, easy metastatic ability, and chemoresistance. Patients with PC have an extremely low survival rate due to the difficulty in early diagnosis. It is estimated that nearly 90% of PC cases are caused by environmental risk factors. Approximately 50% of PC cases are induced by an unhealthy diet, which can be avoided. Given this large attribution to diet, numerous studies have assessed the relationship between various dietary factors and PC. This article reviews three beneficial diets: a ketogenic diet (KD), a Mediterranean diet (MD), and a low-sugar diet. Their composition and impact mechanism are summarized and discussed. The associations between these three diets and PC were analyzed, and we aimed to provide more help and new insights for the prevention and treatment of PC.
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Affiliation(s)
- Yang Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Tao Zhang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenbo Yang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongze Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xinglong Geng
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Guanqun Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hua Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yongwei Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Le Li
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China.,Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Harbin, China
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18
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Wong W, Alouani E, Wei A, Ryu YK, Chabot JA, Manji GA. Future of immunotherapy in pancreas cancer and the trials, tribulations and successes thus far. Semin Oncol 2021; 48:57-68. [PMID: 33965249 DOI: 10.1053/j.seminoncol.2021.02.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 11/11/2022]
Abstract
Pancreas ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of 10%. Currently, chemotherapy remains the standard of care for systemic treatment. Immunotherapy with checkpoint inhibitors unfortunately has not been found to be effective in the treatment of PDAC to date, likely due to the highly desmoplastic and immunosuppressive tumor microenvironment (TME). Treatment targeting pathways against the immunosuppressive mechanisms of PDAC are of mounting interest to improve outcomes in PDAC. In this review, we discuss prior efforts and the current state of immunotherapy in PDAC. We will also review the emerging targets and treatments with significant clinical potential for the treatment of PDAC such as: CD40 pathway, the adenosine pathway, the CXCR4/CXCL12 axis, the CCR2/CCL2 axis, IDO pathway, and others.
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Affiliation(s)
- Winston Wong
- Division of Hematology and Oncology, Columbia University Irving Medical Center, and New York Presbyterian Hospital, New York, NY
| | - Emily Alouani
- Division of Hematology and Oncology, Columbia University Irving Medical Center, and New York Presbyterian Hospital, New York, NY
| | - Alexander Wei
- Division of Hematology and Oncology, Columbia University Irving Medical Center, and New York Presbyterian Hospital, New York, NY
| | - Yun Kyoung Ryu
- Division of Hematology and Oncology, Columbia University Irving Medical Center, and New York Presbyterian Hospital, New York, NY
| | - John A Chabot
- Division of Hematology and Oncology, Columbia University Irving Medical Center, and New York Presbyterian Hospital, New York, NY
| | - Gulam A Manji
- Division of Hematology and Oncology, Columbia University Irving Medical Center, and New York Presbyterian Hospital, New York, NY.
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