Project 3: Targeting Stress-induced MK2 as Novel Strategy in Pancreatic Cancer

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PROJECT SUMMARY We propose a phase 1 clinical trial to test the safety and preliminary efficacy of a new therapeutic strategy that aims at augmenting the efficacy of standard chemotherapy in pancreatic cancer. To date, combination chemotherapies remain the mainstay treatment of pancreatic cancer. FOLFIRINOX is a combination chemotherapy regimen with the best track record for treatment of pancreatic cancer that cannot be treated with surgery; however, even with the best treatment, the majority of the patients will still succumb to the disease within one to two years of diagnosis. This is in part due to pancreatic cancer cells developing resistance to the chemotherapy drugs. Another reason for poor survival and unsuccessful clinical experience of immunotherapy is because of the dense non-cancer cells that surround the pancreatic cancer not only prevent the chemotherapy drugs from reaching the cancer cells, but also incapacitate anti-tumor immune cells. These challenges support the need for further research into overcoming resistance to combination chemotherapy and improving the effect of immunotherapy in pancreatic cancer. Using an unbiased protein array analysis, we found that pancreas cancer cells dramatically upregulate MK2 enzyme and its partnering molecule Hsp27, when exposed to FOLFIRINOX chemotherapy. Both MK2 and Hsp27 protect pancreas cancer cells from cell death when their DNA is hit by chemotherapy. When MK2 was blocked by ATI-450, pancreatic cancer cells became much more vulnerable to chemotherapy-induced death. In an aggressive pancreas cancer mouse model (KPC mice), the combination of ATI-450 plus FOLFIRINOX potently ablated the cancer, an observation that to our best knowledge, has not been reported. Furthermore, ATI-450 causes immune cells surrounding the cancer to be converted to the types that were more susceptible to immunotherapy, paving the way for development of an immunotherapy regimen, which we will establish in this proposal. Importantly ATI-450 is now already in clinical trial for patients with moderate to severe rheumatoid arthritis and is very well-tolerated except for infrequent, mild dizziness and headaches, which lessens our concerns of added toxicities when combined with FOLFIRINOX. In this proposal, we will conduct a phase I clinical trial to establish the safety of combining ATI-450 with FOLFIRINOX in patients with inoperable pancreatic cancer (Aim 1). We will determine a safe, tolerable dose of ATI-450 in combination with FOLFIRINOX and get an early indication on whether this combination is more effective than FOFIRINOX alone. We plan to obtain tumor and blood samples in patients who are receiving ATI- 450 and FOLFIRINOX on this trial and analyze those to confirm that the addition of ATI-450 was useful to overcome the resistance to FOLFIRINOX, and changed the immune cells surrounding the cancer, as it did in animal models (Aim 2). Lastly, we made discovery that MK2 activates anti-cancer immunity. By analyzing patient samples treated with MK2 inhibitor and generating new state-of-the art genetic mouse models, we will investigate the mechanism and develop a novel MK2 inhibitor-based immunotherapy strategy for pancreatic cancer (Aim 3).