Noncanonical Function and Regulation of the Unfolded Protein Response in Mutant KRAS-Driven Pancreatic Ductal Adenocarcinoma
Abstract
Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Pancreatic Cancer; PRCRP Military Relevance Focus Areas: Gaps in cancer treatment and/or survivorship that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public. In 2018 alone, 53,670 people in the United Sates will be diagnosed with pancreatic cancer and 80% (43,090) of them will die of this disease. The median survival for pancreatic cancer patients is less than 6 months and the 5-year survival rate is only 3% to 5%. The poor prognosis of pancreatic cancer is attributable to its tendency for late presentation, aggressive local invasion, early metastasis, and poor response to chemotherapy. The oncogene KRAS mutation is found in >90% of human pancreatic cancers and is the driver of this devastating disease. Although extensive research has identified oncogenic KRAS-regulated signaling pathways, treatment with drugs targeting these individual effector pathways in clinical trials has resulted in the rapid activation of compensatory pathways, ultimately leading to therapy resistance and cancer relapse. Thus, pancreatic cancer is an incurable disease; there is an urgent need to better understand KRAS biology to develop effective therapies for pancreatic cancer patients. Our recent preclinical studies reveal the IRE1a/XBP1 pathway as a novel therapeutic vulnerability for KRAS-driven pancreatic cancer. IRE1a/XBP1 is part of an intricate signaling network of the stress sensing and adapting mechanism called the Unfolded Protein Response. We found multiple KRAS regulated pathways converge on the IRE1a/XBP1 and rely on it to survive. Therefore, targeting the IRE1a/XBP1 pathway has the potential to shut down most major KRAS regulated signaling and overcome the therapy resistance. We have identified a highly specific and potent drug, called 8866, that could efficiently shut down the IRE1a/XBP1 pathway. As a proof-of-concept, while the first-line treatment drug gemcitabine used in the clinic had no effect on the pancreatic cancer progression in the preclinical mouse model, our new drug 8866 was able to stop pancreatic cancer progression and substantially prolong the overall survival of the tumor bearing mice. Importantly, this drug is safe and does not cause any damage to normal organs. The mice well tolerated long-term treatment (50 weeks) of the drug. These promising preclinical data strongly suggest that the mutant KRAS regulated IRE1a/XBP1 pathway is a highly valuable drug target for treating pancreatic cancer, the novel drug targeting this pathway is much more efficacious than the existing first-line treatments for pancreatic cancer. The scientific objectives of this proposal are to establish the biological significance and molecular mechanisms of the KRAS regulated IRE1a/XBP1 pathway and develop novel and effective therapies for immediate clinical application for pancreatic cancer patients. Based on our proof-of-concept preclinical data, the proposed study will move beyond just minor improvement of currently approved therapies in clinic, but rather will highly likely revolutionize the treatment regimens for pancreatic cancer patients and substantially extend their lives. This study will also significantly advance the field of pancreatic cancer research by elucidating an unprecedented therapy resistance mechanism. The clinical impact of this proposal is immediate, as this drug 8866 is expected to move into phase I clinical trial in 2019. If proven effective, the near-term impact of this proposal may extend well beyond pancreatic cancer and will offer a new therapy for other KRAS-driven malignancies such as lung cancer and colorectal cancer. Military personnel have higher risk of pancreatic cancer because of the occupational exposure to cancer risk factors. This proposal will fill in the gap of ineffective treatments and poor survivorship for military pancreatic cancer patients. The proposed
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910524
Entities
People
- Xi Chen
Organizations
- Baylor College of Medicine
- United States Army