Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. The Western diet is associated with CRC, and common KRAS mutations are associated with worse prognosis. Rectal adenocarcinoma (READ) makes up one-third of all CRC cases, and radiotherapy is part of the mainstay of treatment for stages II-III READ patients. However, radiotherapy results in gastrointestinal (GI) toxicities. Dietary methionine restriction (MR; ~80% decrease), synergizes with RT in in vivo and in vitro KRASmut models. Our results show that MR significantly changes KRAS protein expression and is associated with decreased GI inflammation. Hence, we hypothesize that MR synergizes with RT to cause lethal cell damage specifically in KRASmut cancer cells while protecting KRASwt bowel epithelium from radiation-induced toxicity via reduced inflammation. We propose to study the impact of MR on radiation sensitivity in KRASmut and wt READ. We will leverage the small animal radiation research platform to model the clinical standard of care, as well as the pathology and flow cytometry cores. Our results will provide the foundation for studying MR in combination with radiation in a phase I clinical trial of READ patients. These results will be translatable to KRAS mutant-driven malignancies where normal tissue toxicities from radiation are dose-limiting, such as pancreatic and lung cancer. In this project, Dr. Wolfe is providing the expertise in the clinical and experimental aspect of READ and KRAS mutations, while Dr. Miousse contributes her expertise in the effect of MR and radiation on cancer and GI tissues.

2021-04-01

2023-03-31