Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a poor prognosis and accounts for upwards of 95% of all pancreatic cancers. With the rise in incidence, PDAC will soon be the second leading cause of cancer-related deaths in the United States. Despite recent progress in the development of more effective combinatorial chemotherapy treatments, survival has remained poor because of chemotherapy- associated toxicity, inherent or acquired chemoresistance, and the lack of biomarkers to match patients with specific chemotherapeutic agents. Oncolytic virotherapy (alone or as a part of a combination treatment) is a relatively new anticancer approach that utilizes replication-competent viruses to infect and destroy cancer cells (without damaging normal tissues) through virus replication and virus-induced antitumor immune responses. Vesicular stomatitis virus (VSV) is one such oncolytic virus (OV) and is already in phase I clinical trials against different malignancies. In our previous studies, we analyzed various VSV-based OVs against many PDAC cell lines and made an initial characterization of PDAC lines regarding their general cellular characteristics and permissiveness to VSV. Our studies demonstrated that VSV is effective against the majority of tested human PDAC cell lines. However, some PDAC cell lines show various degrees of resistance to VSV and other OVs, mainly due to residual or upregulated JAK/STAT antiviral signaling or inefficient attachment of viruses to some PDACs. Our goal is to better understand and target factors determining the success of VSV-based OV therapy, enhance OV efficacy, overcome the resistance of PDACs to OVs, and broaden the spectrum of PDAC phenotypes to which this treatment can be successfully applied. This proposal is based on our recently published and preliminary studies using an experimental evolution approach. Using this approach, we have generated novel PDAC-targeted oncolytic VSV variants that are better able to infect and kill PDAC cells without harming non-malignant cells. In Aim 1, we will determine molecular mechanisms responsible for the improved oncoselectivity of these novel viruses. In Aim 2, we will examine the efficacy and safety of our state-of-the-art virus VSV-p53-CCSUIT-2 alone or in combination with FDA-approved drug Ruxolitinib (Jakafi, a selective JAK1 and JAK2 inhibitor) and/or anti-PD-1 antibody using clinically-relevant immunocompetent orthotopic mouse models of PDAC. The triple [VSV-p53-CCSUIT-2/Ruxolitinib/anti-PD-1 antibody] combination is expected to increase not only VSV replication and virus-mediated direct oncolysis via Ruxolitinib-mediated inhibition of Type I IFN antiviral signaling, but also anti-PD-1 immunotherapy efficacy via Ruxolitinib-mediated inhibition of JAK- STAT-mediated tumor-protective responses. Our studies will lead to the development of more effective VSV- based oncolytic therapies and broaden the spectrum of PDAC phenotypes to which this treatment can be successfully applied. While this proposal is focused on VSV against PDAC, our discoveries will also be relevant to other OVs and tumor systems.
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