Project 4: Effect of Meal Timing during Cancer Treatment in Alaska Native Patients - A Randomized Clinical Trial

PROJECT SUMMARY/ABSTRACT – Project 4 A promising strategy for reducing toxicity and improving the efficacy of anticancer treatments involves combining treatment with fasting regimens. Fasting is thought to sensitize tumor cells to the cytotoxic effects of treatment, while protecting healthy cells by increasing stress resistance. In addition, fasting is associated with improved

metabolic health. The overarching goal of this project is to test time-restricted eating (TRE) during cancer treatment in an understudied population at high risk for metabolic dysregulation. Alaska Native people suffer disproportionately from metabolic disease and have the highest colorectal cancer incidence and mortality rates

of any racial and ethnic group in the world. This proposed clinical trial builds on the research infrastructure of, and lessons learned from, our P20 SPORE planning grant (P20CA252733) and our ongoing randomized clinical trial of TRE in patients with rectal cancer (CHRONO Trial, R01CA258222, NCT04722341). While the CHRONO

Trial is recruiting racially and ethnically diverse patients in Los Angeles, CA and Birmingham, AL, it will unlikely include any Alaska Native patients. We hypothesize that TRE may be more beneficial in the Alaska Native community given their high rates of metabolic diseases. Therefore, in this SPORE Project we will conduct a

parallel randomized Phase II trial with a 1:1 (TRE:control) allocation ratio in 100 patients with rectal cancer receiving neoadjuvant treatment at the Alaska Native Medical Center (ANMC) which is part of the Alaska Native Tribal Health Consortium (ANTHC). ANTHC is the largest Native-owned health services organization in the U.S.,

providing comprehensive health care to >180,000 Alaska Native people. The intervention [TRE arm: 8 hours eating / 16 hours fasting per day (6+ days a week); control arm: 12+ hour window of eating per day] will occur during the treatment period (approximately 6 months). Our endpoints of interest are pathological complete

response (pCR), treatment-related toxicities, health-related quality of life (HR-QOL) and adherence (Aim 1). We hypothesize that TRE will enhance pCR rates, decrease treatment-related toxicity, and improve QOL compared to the control arm and will be a feasible intervention with high adherence in this patient population. In Aim 2, we

will quantify therapy-induced DNA damage in leukocytes to evaluate TRE's mechanistic effects in protecting healthy cells according to the differential stress sensitization theory. We also will evaluate differences in five selected intermediate biomarkers related to metabolic function and cancer (IGF-1, IGF-B3, insulin, glucose and

CRP) and conduct an exploratory analysis of tumor tissue biomarkers using nanoString GeoMx®. In Aim 3, we will compare findings among Alaska Native people with those from African American, Asian, Hispanic, and non- Hispanic White individuals through a horizontal collaboration with the CHRONO Trial. The data garnered will

help determine the clinical utility of TRE among Alaska Native patients with rectal cancer, a population that continues to experience considerable health disparities.