Shailendra K. Gautam, PhD

Pancreatic cancer (PC) is the deadliest cancer of the gastrointestinal tract causing the worst five-year survival rate of ~10% in the USA. Due to low mutation burden, immunosuppressive tumor microenvironment (TME), and high desmoplasia, pancreatic tumors are poorly immunogenic, show poor immune infiltration, and are difficult to penetrate by systemic therapies. Our group has been optimizing mucin-targeted therapies and immunotherapies in state-of-the-art preclinical models of PC. As MUC4 is a novel tumor antigen, we have optimized different nano-delivery platforms to induce a therapeutically significant anti-tumor immune response. Our research showed that MUC4 nanovaccine enhances dendritic cell activation, improves antigen presentation, and elicits a Th1-type immune response. As a complementary therapeutic approach, we focused on modulating tumor stroma to enhance immune infiltration and delivery of systemic therapies. We have targeted the endothelin (ET)-axis, constituted by ET-receptors A and B and their common ligand ET-1, which is expressed differentially by different cellular components of pancreatic tumors. We found that targeting with dual ET-receptor antagonist bosentan improved tumor perfusion and the efficacy of chemotherapeutic agents and enhanced immune infiltration in murine models of PC. Our future goal is to combine these therapeutic strategies, such as MUC4 nanovaccine and ET-axis antagonists with PC chemotherapies, to achieve a clinically significant therapeutic response.

As the experimental murine models are the core component of preclinical optimization of novel therapeutic approaches, our primary goal is to develop clinically relevant murine models that could recapitulate stages-specific pathological hallmarks of pancreatic and breast cancers, including tumor stroma, immunosuppression, and cancer-specific metastatic progression. Besides utilizing different genetically engineered mice, we have developed and used subcutaneous and orthotopic tumor models of pancreatic and breast cancer, hemispleen injection model of liver metastasis, immunocompetent KPC homograft model, cancer cell-fibroblast co-implantation model to evaluate targeted therapies and immunotherapy. However, our endeavors in the future will be directed toward developing clinically relevant genetically engineered mice and experimental murine models specific to early disease progression, disease recurrence, and organ-specific metastasis.

Following our research interest in breast cancer metastasis, we are aimed to optimize preventive therapeutic approaches to delay metastatic progression in breast cancer. Particularly, kinases are the major regulators of oncogenic progression and metastasis. Our investigation suggested that kinases such as the EGFR, cMET, and Focal adhesion kinase (FAK) coordinate to aggravate breast cancer brain metastasis (BC-BrM), the most lethal metastatic progression in breast cancer. We observed that targeting the EGFR-cMET axis not only reduced primary tumor burden but also inhibited brain metastases significantly in a novel orthotopic model of BC-BrM. Our future goal is to investigate whether targeting these kinases could sensitize chemotherapy or elicit a synergistic effect on BC-BrM. In addition, we will extend our investigation to elucidate if these anti-kinase therapies can deliver stroma and immune modulatory effects to improve the therapeutic efficacy of conventional treatments in metastatic breast cancer.