Combining the Newcastle disease oncolytic virus and KRAS inhibitors to overcome stromal barriers in pancreatic ductal adenocarcinoma.

• Grant number: 24/07722-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2024
• End date: July 31, 2025
• Field of knowledge: Biological Sciences - Biology
• Principal Investigator: Pedro Luiz Porfirio Xavier
• Grantee: Letícia Bottin Freires
• Host Institution: Faculdade de Zootecnia e Engenharia de Alimentos (FZEA). Universidade de São Paulo (USP). Pirassununga , SP, Brazil

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancer types due to it aggressiveness and difficulty in obtaining early diagnosis. Furthermore, one of the main reasons for high mortality rates is resistance to conventional therapies, such as chemotherapy. The KRAS gene is frequently mutated in PDAC and is considered a potential therapeutic target. Recently, some KRAS inhibitors for different KRAS mutations have been developed. However, some studies have demonstrated that PDAC can develop resistance to these inhibitors and new therapeutic approaches that can overcome acquired resistance, working synergistically with KRAS inhibitors are fundamental. Newcastle disease virus (NDV) is an oncolytic virus representing a promising strategy for the treatment of PDAC due to its ability to selectively replicate in tumor cells and induce immunogenicity. Furthermore, as well as other oncolytic viruses, NDV could infect and damage the dense tumor stroma present in PDAC, helping to overcome the stromal barrier and increasing the effectiveness of other therapeutic agents. Thus, this project proposes to evaluate the synergistic effect between the NDV virus and KRAS inhibitors, observing the ability of the NVD virus to infect stromal stellate fibroblasts and cancer cells of PDAC spheroid models cultured in a specific tissue hydrogel (PDAC-F). Firstly, using cell viability assays and fluorescence microscopy, it will be possible to observe whether the NDV virus, individually, can infect PDAC-F spheroids and promote oncolytic effects. Furthermore, using immunofluorescence assays, it will be possible to observe whether the NDV virus can reduce extracellular matrix components such as collagen I. Finally, through cell viability assay, it will be possible to observe whether combined therapy has a synergistic effect using the NDV virus and the KRAS inhibitors Sotorasib, MRTX1133, and BI-2865. The findings observed in this study will provide initial insights regarding the mechanisms by which the NDV virus can infect the dense PDAC stroma, becoming a strong synergistic tool in conjunction with KRAS inhibitors and other antineoplastic agents.