Pancreatic cancer has the lowest survival rate among human cancer types and is one of the most resistant cancers to traditional therapies, such as chemotherapy, radiotherapy and targeted therapy. Immunotherapy has had remarkable efficacy in many cancer types but has not gained much success in pancreatic cancer. Notably, nearly every human pancreatic cancer contains activating mutations in the KRAS gene, which drive the development and maintenance of the disease. Thus, mKRAS has been one of the most desirable drug targets in the pharmaceutical industry. After decades of failure, inhibitors specifically targeting KRAS have recently entered clinical trials and demonstrated promising clinical b...

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Pancreatic cancer has the lowest survival rate among human cancer types and is one of the most resistant cancers to traditional therapies, such as chemotherapy, radiotherapy and targeted therapy. Immunotherapy has had remarkable efficacy in many cancer types but has not gained much success in pancreatic cancer. Notably, nearly every human pancreatic cancer contains activating mutations in the KRAS gene, which drive the development and maintenance of the disease. Thus, mKRAS has been one of the most desirable drug targets in the pharmaceutical industry. After decades of failure, inhibitors specifically targeting KRAS have recently entered clinical trials and demonstrated promising clinical benefit. However, the duration of response is short among all treated patients, due to the development of resistance to KRAS therapy and KRAS-independent tumor maintenance. Given such therapeutic challenge, we must aim at identifying and targeting players that are essential for those therapy-resistant tumors. To this end, we have recently generated a new therapeutic approach that targets a unique way for pancreatic cancer to scavenge "food" to fuel their growth and enable tumors maintenance even upon treatment. In addition, our new therapeutic agent can also harness the immune system to kill tumor cells. In this proposal, we will determine the utility of this newly generated agent as a potential therapeutic approach in future clinic application to treat pancreatic cancer. We envision that our evaluation of the new therapeutic approach will open new research horizons for combinations with KRAS inhibitors or other therapies which may have broad implications for pancreatic cancer, and quite possibly other KRAS-mutated tumors. Moreover, we are confident that this research will have profound impact toward the mission of CPRIT, "finding cures and treatments for cancer", by exploring this novel therapeutic agent that may be beneficial for a majority of patients with KRAS mutation.

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