Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

Feldmann, Georg

doi:10.1159/000493437

Cited by 12 publications

(7 citation statements)

References 107 publications

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“…For PDAC, survival rates have not changed significantly in the recent years and also treatment with immune checkpoint inhibitors did not achieve improvements as observed in other tumor entities (67). To enhance overall responsiveness of immunotherapy, several clinical trials have started to combine treatment with immune checkpoint inhibitors together with galectin-3 inhibitor DG-MD-02 or GR-MD02 to enhance therapeutic effects in other tumor entities (42).…”

Section: Discussionmentioning

confidence: 99%

Galectin-3 Released by Pancreatic Ductal Adenocarcinoma Suppresses γδ T Cell Proliferation but Not Their Cytotoxicity

et al. 2020

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment with a dense desmoplastic stroma. The expression of β-galactoside-binding protein galectin-3 is regarded as an intrinsic tumor escape mechanism for inhibition of tumor-infiltrating T cell function. In this study, we demonstrated that galectin-3 is expressed by PDAC and by γδ or αβ T cells but is only released in small amounts by either cell population. Interestingly, large amounts of galectin-3 were released during the co-culture of allogeneic in vitro expanded or allogeneic or autologous resting T cells with PDAC cells. By focusing on the co-culture of tumor cells and γδ T cells, we observed that knockdown of galectin-3 in tumor cells identified these cells as the source of secreted galectin-3. Galectin-3 released by tumor cells or addition of physiological concentrations of recombinant galectin-3 did neither further inhibit the impaired γδ T cell cytotoxicity against PDAC cells nor did it induce cell death of in vitro expanded γδ T cells. Initial proliferation of resting peripheral blood and tumor-infiltrating Vδ2-expressing γδ T cells was impaired by galectin-3 in a cell-cell-contact dependent manner. The interaction of galectin-3 with α3β1 integrin expressed by Vδ2 γδ T cells was involved in the inhibition of γδ T cell proliferation. The addition of bispecific antibodies targeting γδ T cells to PDAC cells enhanced their cytotoxic activity independent of the galectin-3 release. These results are of high relevance in the context of an in vivo application of bispecific antibodies which can enhance cytotoxic activity of γδ T cells against tumor cells but probably not their proliferation when galectin-3 is present. In contrast, adoptive transfer of in vitro expanded γδ T cells together with bispecific antibodies will enhance γδ T cell cytotoxicity and overcomes the immunosuppressive function of galectin-3.

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Section: Discussionmentioning

confidence: 99%

Galectin-3 Released by Pancreatic Ductal Adenocarcinoma Suppresses γδ T Cell Proliferation but Not Their Cytotoxicity

et al. 2020

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“…The majority of PC cases (over 85%) are attributed to pancreatic ductal adenocarcinoma (PDAC) [1]. Due to the frequently late diagnosis, the suboptimal efficacy of available therapies, and the unpredictable progression, the five-year overall survival rate of PC is smaller than 5% and the life expectancy of advanced PC is only 3-6 months [2,3].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression

Romanò

Picca

Eusebi

et al. 2021

Cells

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Pancreatic cancer (PC) is among the most devastating digestive tract cancers worldwide. This cancer is characterized by poor diagnostic detection, lack of therapy, and difficulty in predicting tumorigenesis progression. Although mutations of key oncogenes and oncosuppressor involved in tumor growth and in immunosurveillance escape are known, the underlying mechanisms that orchestrate PC initiation and progression are poorly understood or still under debate. In recent years, the attention of many researchers has been concentrated on the role of extracellular vesicles and of a particular subset of extracellular vesicles, known as exosomes. Literature data report that these nanovesicles are able to deliver their cargos to recipient cells playing key roles in the pathogenesis and progression of many pancreatic precancerous conditions. In this review, we have summarized and discussed principal cargos of extracellular vesicles characterized in PC, such as miRNAs, lncRNAs, and several proteins, to offer a systematic overview of their function in PC progression. The study of extracellular vesicles is allowing to understand that investigation of their secretion and analysis of their content might represent a new and potential diagnostic and prognostic tools for PC.

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“…Ras signaling is a major junction of various signaling pathways. For this reason, Ras and its effectors serve as important targets for therapeutic intervention in pancreatic cancer [23]. SAL is a synthetic Ras inhibitor that affects Ras-membrane interactions and has been shown to effectively inhibit the growth of human cancer cells [10,11,12,13].…”

Section: Discussionmentioning

confidence: 99%

Celecoxib combined with salirasib strongly inhibits pancreatic cancer cells in 2D and 3D cultures

Li¹,

Ma²,

Liu³

et al. 2020

Int. J. Med. Sci.

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Background/Aim: Pancreatic adenocarcinoma is a highly malignant tumor. Synergistic combinations of anticancer agents for the effective treatment of pancreatic cancer patients are urgently needed. Here, we investigated the combined effect of celecoxib (CEL) and salirasib (SAL) on pancreatic cancer cells. Methods: Cell viability and apoptosis were measured by the trypan blue assay, three-dimensional cultures, propidium iodide staining, and caspase-3 assay. NF-κB activation and the protein levels of Akt, pAkt, and Bcl-2 were determined by the luciferase reporter assay and western blot. Results: Co-treatment with CEL and SAL had stronger effects on decreasing cell viability and inducing apoptosis in Panc-1 cells as compared with each agent individually. This combination strongly inhibited NF-κB activity and reduced pAkt and Bcl-2 levels in Panc-1 cells. Conclusion: SAL in combination with CEL may represent a new approach for effective inhibition of pancreatic cancer.

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Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

Cited by 12 publications

References 107 publications

Galectin-3 Released by Pancreatic Ductal Adenocarcinoma Suppresses γδ T Cell Proliferation but Not Their Cytotoxicity

Galectin-3 Released by Pancreatic Ductal Adenocarcinoma Suppresses γδ T Cell Proliferation but Not Their Cytotoxicity

Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression

Celecoxib combined with salirasib strongly inhibits pancreatic cancer cells in 2D and 3D cultures

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