Pancreatic Cancer Treatment: Immunotherapy, Chemotherapy, Chemoradiation, and Targeted Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (25 January 2025) | Viewed by 1794

Special Issue Editors


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Guest Editor
Division of Surgery, Orthopedics and Oncology (KOO), Linköping University Hospital, Linköping, Sweden
Interests: pancreatic cancer; pre-metastatic niche; metastasis; tumor immunology; immunotherapy; chemoradiation therapy

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Guest Editor
Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
Interests: pancreatic cancer; pancreatic cystic lesions; immunotherapy; chemotherapy; chemoradiation therapy

Special Issue Information

Dear Colleagues,

Diagnosis of pancreatic cancer is an issue of grave concern and is tied to poor prognosis. Despite substantial progress in the molecular understanding of this tumor entity on different levels, including genetics and epigenetics, transcriptomics, oncogenic signaling, tumor metabolism, and tumor microenvironment, successful clinical translation, and thus, benefits to patients have been marginal. Emerging evidence suggests that cancer cells disseminate early on and remain dormant, eventually yielding micrometastases soon after surgical resection. Recognition of this phenomenon has given increasing merit to the application of therapeutic approaches targeting the entire organism (such as systemic chemotherapy) in cases of localized disease, in the form of neoadjuvant therapy. The introduction of (m)FOLFIRINOX combination chemotherapy has not only opened new avenues in palliative and adjuvant settings, but it also demonstrates remarkable neoadjuvant potency, enabling the downsizing and resection of locally advanced tumors, altering surgical strategies in the process. Furthermore, a first meaningful targeted therapy concept has been established with PARP inhibition as a maintenance therapy after first-line platinum-based chemotherapy for a small subgroup of patients with germline BRCA mutations. However, uncertainty remains on the ideal type(s) of locoregional and systemic therapy, the optimal doses, sequencing, and combination with other treatment modalities such as radiation, immunotherapy, and targeted therapies.

The continuous improvement in interdisciplinary care within multimodal therapeutic concepts and the implementation of personalized treatment approaches harnessing molecular insights will be vital for further substantial progress and meaningful impact on patients’ survival. As an example, the organoid-based, pharmacogenetically instructed stratification of induction, adjuvant, or palliative therapy concepts is currently being explored. Furthermore, the value of radiotherapy in neoadjuvant, intraoperative, and local recurrence settings awaits clarification.

This Special Issue aims to provide a platform for sharing the recent advancements in preclinical and clinical studies in the form of original studies, systematic reviews/meta-analyses, as well as review articles, pertaining to different treatment modalities in localized resectable, borderline resectable, locally advanced, or metastatic pancreatic cancer. This Special Issue will also focus on basic, translational, and clinical developments, highlighting interdisciplinary approaches, including neoadjuvant and adjuvant chemotherapy, (neo-) adjuvant and intraoperative radio- (chemo-) therapy, and targeted immunotherapy, as well as upcoming trends in treatment for pancreatic cancer. In addition, studies relating to the use of biomarkers to guide the best treatment approach in the form of personalized therapy and/or response to treatment are also welcome.

Dr. Constantinos Zambirinis
Dr. Brett Ecker
Guest Editors

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Keywords

  • pancreatic cancer
  • pancreatic ductal adenocarcinoma
  • actionable molecular mechanisms
  • translational
  • resection
  • radiation therapy
  • chemotherapy
  • immunotherapy
  • multimodal
  • personalized medicine
  • metastasis
  • systemic therapy
  • locoregional therapy
  • KRAS inhibitors
  • PARP inhibitors

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Published Papers (2 papers)

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Research

28 pages, 4289 KiB  
Article
The Combination of Oncolytic Virus and Antibody Blockade of TGF-β Enhances the Efficacy of αvβ6-Targeting CAR T Cells Against Pancreatic Cancer in an Immunocompetent Model
by Zuoyi Zhao, Lauren C. Cutmore, Renato B. Baleeiro, Joseph J. Hartlebury, Nicholas Brown, Louisa Chard-Dunmall, Nicholas Lemoine, Yaohe Wang and John F. Marshall
Cancers 2025, 17(9), 1534; https://doi.org/10.3390/cancers17091534 - 30 Apr 2025
Viewed by 565
Abstract
Background/Objectives: CAR T cell therapy, as a rapidly advancing immuno-oncology modality, has achieved significant success in the treatment of leukaemia and lymphoma. However, its application in solid tumours remains limited. The challenges include the heterogeneity of tumours, local immunosuppression, poor trafficking and infiltration, [...] Read more.
Background/Objectives: CAR T cell therapy, as a rapidly advancing immuno-oncology modality, has achieved significant success in the treatment of leukaemia and lymphoma. However, its application in solid tumours remains limited. The challenges include the heterogeneity of tumours, local immunosuppression, poor trafficking and infiltration, life-threatening toxicity and the lack of precise representative immunocompetent research models. Considering its typically dense and immunosuppressive tumour microenvironment (TME) and early metastasis, pancreatic ductal adenocarcinoma (PDAC) was employed as a model to address the challenges that hinder CAR T cell therapies against solid tumours and to expand immunotherapeutic options for advanced disease. Methods: A novel murine A20FMDV2 (A20) CAR T cell targeting integrin αvβ6 (mA20CART) was developed, demonstrating efficient and specific on-target cytotoxicity. The mA20CART cell as a monotherapy for orthotopic pancreatic cancer in an immunocompetent model demonstrated modest efficacy. Therefore, a novel triple therapy regimen, combining mA20CART cells with oncolytic vaccinia virus encoding IL-21 and a TGF-β-blocking antibody was evaluated in vivo. Results: The triple therapy improved overall survival, improved the safety profile of the CAR T cell therapy, attenuated metastasis and enhanced T cell infiltration. Notably, the potency of mA20CART was dependent on IL-2 supplementation. Conclusions: This study presents an αvβ6-targeting murine CAR T cell, offering a novel approach to developing CAR T cell technologies for solid tumours and a potential adjuvant therapy for pancreatic cancer. Full article
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18 pages, 2327 KiB  
Article
Combined Omipalisib and MAPK Inhibition Suppress PDAC Growth
by Bailey A. Bye, Jarrid L. Jack, Alexandra Pierce, Richard McKinnon Walsh, Austin E. Eades, Prabhakar Chalise, Appolinaire Olou and Michael N. VanSaun
Cancers 2025, 17(7), 1152; https://doi.org/10.3390/cancers17071152 - 29 Mar 2025
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Abstract
Background: Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS, as well as downstream MAPK pathway effectors, have shown limited clinical success. While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known [...] Read more.
Background: Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS, as well as downstream MAPK pathway effectors, have shown limited clinical success. While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Methods: Our therapeutic study targeted the PI3K pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with two different MAPK pathway inhibitors: Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099; SHP2 inhibitor). Western blot analysis demonstrated that the application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT). Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MAPK and PI3K-AKT, and effectively suppress PDAC growth. Results: In vitro studies demonstrated that, in several cell lines, both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. In vivo oral administration of combined Omipalisib/Trametinib treatment was significantly more effective than Omipalisib/SHP099 in reducing implanted tumor growth, and the Omipalisib/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone. Conclusions: Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers. Full article
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