Targeting the Stroma for Pancreatic Cancer Treatment

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PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies despite the recent paradigm shifting success of immunotherapy noted in many other tumor types. Neoadjuvant strategies in PDAC provide a distinctive opportunity for therapeutic intervention to decrease systemic recurrence, yet this remains a substantial problem for patients undergoing curative intent surgery. The significant desmoplastic stroma, immunosuppressive and T cell barren tumor microenvironment (TME) are obstacles for immunotherapeutic efficacy in PDAC. Yet, the neoadjuvant approach offers a unique advantage for comprehensive and robust analysis of the TME and stroma. This proposal describes a career development plan coupled with a parallel research strategy carefully designed through a neoadjuvant translational approach. This approach is specifically proposed in order to cement an independent career as a leader in translating novel findings of stromal and TME biology into future science-driven clinical trials in PDAC. As an oncologist focused on pancreas cancer, the applicant’s long-term goals are to become a leader in the field of pancreatic cancer with an expertise in translating findings from collaborative laboratory research and patient biospecimen analysis. This mentored Career Development Award proposal is based on a continued focus from previous extensive preclinical and clinical work by the applicant, surrounding a master regulator of the TME, known as focal adhesion kinase (FAK). This proposal is also grounded on a hyperfocus in opportunities for deeper clinical-translational experimental learning, expert mentorship, and intensive didactics that will inform future bedside-to-bench-to-bedside investigation and translation. The proposed work will be conducted under the exceptional mentorship of Dr. Lei Zheng and Dr. Stephen J Pandol, international leaders in pancreatic cancer research. The environment of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, the Bloomberg Kimmel Institute for Cancer Immunotherapy and the Pancreatic Cancer Precision Medicine Center of Excellence is an optimal setting from which the proposed studies can originate novel findings and develop an independent investigator. This five year proposal encompasses: (1) the conduct of a clinical trial to evaluate intratumoral T cell infiltration, clinical response and safety of immunotherapy with anti-PD-1 antibody, pembrolizumab, with or without FAK inhibitor (FAKi), defactinib, following neoadjuvant chemotherapy in subjects with high-risk resectable PDAC, (2) employing a novel multiplex immunohistochemistry technique to examine TME immune mechanisms underlying the response and resistance of pembrolizumab and defactinib, and (3) the investigation of the impact of pembrolizumab with and without defactinib on fibroblast phenotypes and immunomodulation associated with reactive oxygen species in the TME utilizing RNAseq and tumor/fibroblast co-culture. The ultimate goal of this proposal is to be able to generate new hypotheses and develop innovative treatment approaches for patients with PDAC.