Targeting cadherin-11 in pancreatic cancer

Pancreatic cancer is soon to be the second leading cause of cancer-related death with an overall median survival of 8 - 11 months. For 70% of patients, systemic chemotherapy is the only option and this mainly relieves the symptoms and/or slightly extends survival, rather than cures the patients. One of the hallmarks of PDAC is extensive fibrosis that comprises up to 80% of the tumor. Cancer-associated fibroblasts (CAFs) and their deposition of extracellular matrix influences tumor progression, metastasis and therapy resistance. CAFs release growth factors and cytokines that not only influence growth of pancreatic cancer cells, but also affect infiltration of immune cells into the tumor microenvironment (TME). However, depletion of CAFs themselves is just as likely to promote PDAC as inhibit it. Here, we propose the rationale that it is better to modulate crosstalk between CAFs, immune cell infiltrates and cancer cells to limit tumor growth, rather than entirely deplete CAFs from the TME. During disease progression, the stromal compartment of patients with PDAC markedly increases expression of the adhesion molecule cadherin 11 (CDH11), which is not expressed in normal pancreas. CDH11 is also increased in activated fibroblasts associated with chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, pulmonary fibrosis, scleroderma and heart fibrosis. Importantly, Cdh11-/- animals are significantly protected from these diseases. In 2021 we published that CDH11 loss and a small molecule CDH11 inhibitor (SD133) we developed (the subject of the current application) also significantly extended survival in pancreatic cancer-bearing genetically engineered mice. This was accompanied by reduced fibrosis, increased infiltration of anti-tumor immune cells and changes in cytokines. Importantly, SD133 is ineffective in mice lacking T and B cells confirming a role for the adaptive immune system in its mechanism of action. A full patent describing this immunomodulatory role of SD133 was submitted in 2021. In this STTR proposal our objective is to refine therapy with SD133, and assess response in vivo – alone or in combination with chemotherapy or immunotherapy, using state-of-art technologies that are available through our Academic Partner. Our first aim is to establish optimal formulation, dose, administration route and treatment schedule of the first-in-class small molecule inhibitor of CDH11, SD133. To increase the translational value of the study, we will next use two additional animal models, a genetically engineered mouse model of PDAC that closely resembles human disease progression, and selected human PDAC PDX models and humanized mice. Our proposal that CDH11 inhibition modulates extracellular matrix composition, and immunomodulates the pancreatic TME by increasing infiltration of anti-tumor immune cells, and deterring infiltration by immunosuppressive cells is highly innovative. Additionally, we hypothesize that CDH11 inhibition promotes susceptibility to standard-of-care chemotherapy or immunotherapy, for added benefit. Completion of these studies will promote our long-term goal of translating SD133 into a clinical trial for PDAC patients.Pancreatic ductal adenoacarcinoma is one of the most lethal malignancies and is resistant to immunotherapy as the tumor microenvironment is immune suppressive. In this grant we propose to target a host molecule (cadherin-11) that contributes to immunosuppression in pancreatic cancer. Cadherin-11 is also an important target in obesity and inflammatory diseases.