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 a less studied population at high risk for metabolic dysregulation. AN people experience disproportionately high rates of metabolic disease and have the highest colorectal cancer incidence and mortality rates 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 patients in Los Angeles, CA and Birmingham, AL, it will unlikely include any AN patients. We hypothesize that TRE may be more beneficial in the AN people 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 AN Medical Center (ANMC) which is part of the ANTHC. ANTHC is the largest customer-owned health services organization in the U.S., providing comprehensive health care to >180,000 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 AN people with different population groups through a horizontal collaboration with the CHRONO Trial. The data garnered will help determine the clinical utility of TRE among patients with rectal cancer.