Transforming growth factor ? (TGF?) is an attractive therapeutic target in cancer. However, blocking TGF? in pancreatic cancer (PDA) has not been successful in clinical studies. This is due part to the fact that TGF? signaling suppresses pancreatic cancer cell growth in a context- dependent manner. In contrast, TGF? signaling in stromal cells promotes to tumor progression by inducing fibrosis and immunosuppression, characteristics of PDA. Moreover, we have identified TGF?-stimulated fibroblasts produce cytokines that limit innate immune cell activity. For example, IL-6 production by PDA associated fibroblasts reduces NK cell activity that facilitates PDA metastasis. Using species specific tools we demonstrated that selective inhibition of stromal TGF? signaling reduces PDA metastasis in mice bearing PDA xenografts and also promotes an epithelial tumor cell phenotype and an altered immune microenvironment. These observations strongly suggest a TGF?-driven paracrine network between stromal cells and tumor cells in PDA that promotes tumor progression. Up to 60% of human PDA have tumor cell specific deficiency in canonical TGF? signaling via loss of TGF? receptor 2 (TGF?R2) or the downstream signal mediator SMAD4. Here we propose that selective inhibition of TGF? signaling in stromal cells in PDA that harbors epithelial mutations in TGF? signaling will dramatically and safely enhance the efficacy of chemotherapy and/or immune therapy. To delineate the mechanisms involved and test this novel strategy, we propose the following aims: 1, Identify TGF? signaling in cancer associated fibroblasts that drive PDA progression; 2, Determine the effect of stromal TGF? inhibition on the efficacy of chemotherapy and checkpoint blockade in models of TGF? mutant PDA. If proven correct this would provide a rationale to stratify PDA patients such that those with tumor cell mutations in TGF? signaling would be candidates for inhibition of stromal TGF? signaling in combination with standard therapy or immune therapy.
Transforming growth factor ? (TGF?) is an attractive therapeutic target in cancer; however, it has been challenging to effectively and safely inhibit in pancreatic cancer. The relevance to public health of this project is that we aim to provide a rationale and strategy to stratify pancreatic cancer patients such that those with tumor cell mutations in TGF? signaling would be candidates for inhibition of stromal TGF? signaling in combination with standard therapy or immune therapy. This project has the potential to provide benefit to ~60% of patients diagnosed with pancreatic cancer.
