Role of cingulin in FOLFIRINOX resistance

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Abstract Project 3 of the parent grant seeks to determine the role of pancreatic ductal adenocarcinoma (PDAC) molecular subtype and the tumor microenvironment in treatment response in patient sample. Aim 1 of the project evaluates patient outcome based on molecular subtyping guidance through PurIST. Aim 3 of the project determines therapies that target the tumor and stroma. The diversity supplement project expands on results of several sub-aims within Aims 1 and 3. Of the two molecular subtypes defined by PurIST that are being studied, basal-like and classical, the basal-like subtype is resistant to the first-line therapy FOLFIRINOX, the main theme and rationale for Aims 1, 3 in Project 3. We and others have found that there may be plasticity between the classical and basal-like subtype that may be dependent on either signaling, but the regulators of plasticity remain unclear. Relevant to Project 3 Aim 1, the diversity supplement project will determine if patients with basal tumors may become responsive to FOLFIRINOX through restoration of polarity through the gene cingulin. This project will use patient-derived models to first determine if ‘switching’ a basal tumor to a classical phenotype is feasible through alteration of CGN signaling, and second, if CGN overexpression will restore basal tumor sensitivity to FOLFIRINOX. In the long run, results from this project will determine if switching basal tumors to classical will facilitate additional therapeutic opportunities that target the tumor and stroma.