Modulating Neural Signaling in the Treatment of Pancreatic Cancer

Scientific Objective and Rationale: Data from the American Cancer Statistics and the Veterans Affairs Cancer Reports show that pancreatic cancer incidence has increased in both civilian and military cohorts and presents a high risk of mortality in both groups. Furthermore, in 2011, the National Cancer Institute (NCI) studied over 4.5 million U.S. Veterans admitted to Veterans Affairs hospitals and found that Veterans with diabetes have an increased risk of liver and pancreatic cancers and a lower risk of other cancers. The prevalence of these sobering statistics has prompted effort from multiple laboratories to increase the understanding of pancreatic cancer. Apart from lack of early diagnosis, two other aspects needing resolution are: How do pancreatic cancers resist treatment and what can be done to deliver precise and targeted therapy to patients? Many studies now show that the nervous system is intricately involved in cancer. For instance, in most solid tumors such as the breast and the prostate, there is a rich supply of nerves and increased nerve size during cancer growth. Our own work has revealed a strong role for nerves in gastric cancer. Interestingly, through detailed investigation, we demonstrated, using multiple models, that some of the nerves can also act to suppress pancreatic tumor growth. Given that (a) pancreatic cancers have the fastest growth rates among human solid tumors; (b) U.S. Veterans sometimes face an increased risk of dying from metastatic pancreatic cancer compared to civilians because of several factors, including their work-related lifestyle and unique environmental exposure; and (c) pancreatic tumors are among the least responsive to immune checkpoint inhibitors in both military and civilian patient cohorts; there is a requirement for an agent that has multiple modes of action to overcome these problems. We have identified a drug that is Food and Drug Administration (FDA)-approved for humans (currently for GI tract diseases) that already indicates therapeutic potential by addressing the above challenges through its multi-faceted capability of inhibiting tumor formation; decreasing tumor-promotion by myeloid cells; and decreasing metastatic spread of cancer stem cells in the pancreas. We now propose to understand the mechanism of action, the drug's effect on the cells surrounding the tumor, and its evaluation through a Phase II clinical trial. To our knowledge, this is the first study leveraging inhibitory neural pathways to treat a solid malignancy using a drug that is FDA-approved for humans. The overall proposal will address the following FY20 PCARP Focus Areas: I. Understanding precursors, origins, and early progression of pancreatic cancer II. Understanding the events that promote pancreatic cancer metastasis III. Understanding the relationship between oncogenic signaling and the tumor microenvironment that drives drug resistance and therapeutic response IV. New drug development targeted toward cancer sensitivity and resistance mechanisms, including immune mechanisms of resistance Impact: Our Team of investigators will be led by Timothy Wang, M.D., who is Chief of the Division of Digestive Diseases at Columbia University, recipient of the NCI Outstanding Investigator Award, and the leader of our Pancreas Research Program partnering with Dr. Susan Bates, M.D., who has extensive experience in leading clinical trials. She works for Columbia University and the James J. Peters Veterans Administration Center, Bronx, in a collaboration between the NCI and the Veteran Affairs Interagency Group to accelerate trial enrollment (NAVIGATE) of military Veterans in NCI-related studies. Short-Term Impact: Our study will help understand how the nerves and cells surrounding the tumor affects its growth while simultaneously testing the compound that we have identified both alone and in combination with chemotherapy to circumvent therapy-resistant tumors. Becau