Preclinical study of oncolytic adenovirus-mediated cytotoxic gene therapy with gemcitabine for chemoresistance of desmoplastic tumor.

e15507 Background: Pancreatic cancer is a highly lethal disease. Excessive accumulation of tumor extracellular matrix (ECM) and epithelial-to-mesenchymal transition (EMT) phenotype are two main contributors to drug resistance in desmoplastic pancreatic tumors. Methods: To overcome the limitations of various conventional therapeutics against desmoplastic pancreatic cancer, we utilized an oncolytic adenovirus (oAd) for combination therapy with gemcitabine, a standard chemotherapeutic for pancreatic cancer treatment. Here, we report the results of preclinical pharmacology and efficology studies conducted in pancreatic cancer model. Results: Efficacy studies in orthotopic pancreatic xenograft tumor model demonstrated that oAd effectively attenuated tumor cell proliferation. oAd further prevented metastasis of pancreatic cancer and sensitized pancreatic tumor to gemcitabine treatment. Furthermore, oAd augmented drug penetration and dispersion within pancreatic tumor xenografts and patient-derived pancreatic tumor spheroids. These results suggest that oAd enhance the therapeutic effect of chemotherapeutic agent in chemo-resistant and desmoplastic pancreatic tumor, thus overcoming the preexisting limitations of standard treatments. Conclusions: Overall, these results demonstrate that local administration of an oncolytic adenovirus with gemcitabine is well tolerated and support moving this investigational approach into human trials.

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Fe2P nanorods based photothermal therapy combined with immune checkpoint inhibitors for pancreatic cancer

Nanophotonics ◽

10.1515/nanoph-2021-0196 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Shanshan Liu ◽

Jiawen He ◽

Ruixiang Song ◽

Mengmeng Zhang ◽

Lianghao Huang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Photothermal Therapy ◽

Pancreatic Tumor ◽

Local Treatment ◽

Advanced Pancreatic Cancer ◽

Tumor Model ◽

Pancreatic Tumors ◽

Tumor Cell Death ◽

Primary Tumors

Abstract Treatment of pancreatic cancer is faced with great difficulties and challenges due to high lethality and metastasis. Synergism of targeted therapy and immunotherapy has been considered as ideal strategy to both eliminate primary tumors and control metastases. For the treatment of advanced pancreatic cancer, we demonstrated a local photothermal therapy (PTT) following administration of monoclonal antibody of programmed death ligand 1 (αPD-L1). Fe2P nanorods were employed as a Fenton agent and photothermal agent, which modified with DSPE-PEG2000-Mal for improved biocompatibility and Mal mediated-antigen presentation. Under a low dose laser irradiation at 980 nm, Fe2P-PEG-Mal nanorods (NRs) mediated PTT could induce immunogenic tumor cell death that can cause dendritic cells (DCs) infiltration and maturation. In a bilateral pancreatic tumor model, the local treatment of NRs-PTT on primary tumor could cause the increased infiltration of cytotoxic T lymphocytes (CTLs) and decreased residential of M2 macrophages in untreated distal tumors. Furthermore, subsequently intervened αPD-L1 could enhance cell death triggered by CTLs in distal tumors through reversing immunosuppression. An orthotopic pancreatic tumor model was used to further confirm the therapeutic outcome. Finally, the combination of NRs based PTT and αPD-L1 based immunotherapy was able to significantly eliminate orthotopic pancreatic tumors and reduce mesentery metastases. Thus, the strategy may provide a more effective treatment for pancreatic cancer.

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Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment

Cancers ◽

10.3390/cancers13225661 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5661

Author(s):

Sharavan Ramachandran ◽

Itishree S. Kaushik ◽

Sanjay K. Srivastava

Keyword(s):

Pancreatic Cancer ◽

Cancer Patients ◽

Pancreatic Tumor ◽

Tumor Model ◽

Annexin V ◽

Pancreatic Tumors ◽

Transmission Electron Microscopy Analysis ◽

Genomic Databases ◽

Apoptotic Effects

Pancreatic tumors exhibit high basal autophagy compared to that of other cancers. Several studies including those from our laboratory reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we evaluated the autophagy and apoptosis inducing effects of Pimavanserin tartrate (PVT). Autophagic effects of PVT were determined by Acridine Orange assay and Transmission Electron Microscopy analysis. Clinical significance of ULK1 in normal and pancreatic cancer patients was evaluated by R2 and GEPIA cancer genomic databases. Modulation of proteins in autophagy signaling was assessed by Western blotting and Immunofluorescence. Apoptotic effects of PVT was evaluated by Annexin-V/APC assay. Subcutaneous xenograft pancreatic tumor model was used to evaluate the autophagy-mediated apoptotic effects of PVT in vivo. Autophagy was induced upon PVT treatment in pancreatic ducal adenocarcinoma (PDAC) cells. Pancreatic cancer patients exhibit reduced levels of autophagy initiator gene, ULK1, which correlated with reduced patient survival. Interestingly, PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, LC3A/B, and cleavage of caspase-3, an indicator of apoptosis in several PDAC cells. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in PDAC cells. Notably, chloroquine abrogated the growth suppressive effects of PVT by 25% in BxPC3 tumor xenografts in nude mice. Collectively, our results indicate that PVT mediated pancreatic tumor growth suppression was associated with induction of autophagy mediated apoptosis.

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Epithelial to mesenchymal transition and the generation of stem-like cells in pancreatic cancer

Pancreatology ◽

10.1016/j.pan.2013.01.004 ◽

2013 ◽

Vol 13 (2) ◽

pp. 114-117 ◽

Cited By ~ 19

Author(s):

Andrew D. Rhim

Keyword(s):

Pancreatic Cancer ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition

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CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer?

Journal of Oncology ◽

10.1155/2019/9681698 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Alessandra Righetti ◽

Matteo Giulietti ◽

Berina Šabanović ◽

Giulia Occhipinti ◽

Giovanni Principato ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Stromal Cells ◽

Tumor Invasion ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Tumor Development ◽

Physiological Role ◽

Mesenchymal Transition ◽

Splicing Isoforms

CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.

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