Abstract 2465: Optical imaging captures chemo-induced metabolic reprogramming during disease regression
Authors: Sunassee Enakshi Devi , Maydew Elizabeth , Erturk Sultan , Madonna Megan , Crouch Brian , Ramanujam Nirmala 
Published: June 2022

Abstract
Less than 20% of Triple Negative Breast Cancer (TNBC) patients experience long-term responses to mainstay chemotherapy, as tumors develop chemo-resistance. Prediction of chemo-resistance will guide treatment planning, thus improving response while reducing toxicity and cost associated with ineffective therapies. Spatial and temporal metabolic reprogramming holds promise as a biomarker of therapy response as resistant tumor subpopulations utilize alternate metabolic pathways to escape therapy, enter dormancy and recur. Currently, there are no tools to temporally evaluate heterogenous changes along distinct metabolic axes in vivo at a spatial resolution capable of resolving vulnerabilities of residual tumor subpopulations. We developed an optical-imaging based platform to correlate long-term treatment outcomes to early chemo-induced metabolic changes along three relevant axes of TNBC chemoresistance (Glycolysis, Oxidative Phosphorylation and Fatty Acid Oxidation) at high spatial resolutions. Here, we validated our system’s ability to capture metabolic signatures of disease regression that accompany chemo-resistance by assessing metabolic reprogramming and tumor kinetics in MDA-MB-231 TNBC xenografts. Xenografts were established by orthotopic cell injection and mice were treated with Paclitaxel (PTX), a commonly used chemotherapeutic drug in TNBC treatment, under a conventional maximum dose density regimen. Mice were monitored for drug response via caliper measurements. Xenografts were partially sensitive to PTX: tumor kinetics showed an initial response to PTX, a dormancy period, and a resurgence in tumor volume at ~60 days post drug withdrawal (n=3). A separate cohort of mice were implanted with window chambers on the primary tumor and imaged every two days with previously validated fluorophores 2-NBDG, TMRE and Bodipy to directly report on glucose uptake, mitochondrial membrane potential or fatty acid uptake, respectively. Wide field fluorescence imaging showed a significant increase in TMRE as early as two days after the 3rd PTX dose (n=5, p&lt;0.05) and a significant decrease in 2-NBDG as early as two days after 5th PTX dose (n=5, p&lt;0.05). No significant changes in Bodipy were seen. Decreased 2-NBDG and increased TMRE remained up to 40 days after drug withdrawal. Consistent with the literature, our results point towards a metabolic switch from glycolysis to mitochondrial respiration and suggests decreased use of glucose as a metabolic substrate. For this cell line, no altered uptake of fatty acids was detected, possibly suggesting amino acid catabolism as a fuel for mitochondrial respiration. This study confirms our platform’s ability to capture the resulting metabolic changes following chemotherapy and during disease regression. We aim to use this system to visualize and exploit in vivo metabolic vulnerabilities of disease regression that correlate to local and distal recurrences.
Citation Format: Enakshi Devi Sunassee, Elizabeth Maydew, Sultan Erturk, Megan Madonna, Brian Crouch, Nirmala Ramanujam. Optical imaging captures chemo-induced metabolic reprogramming during disease regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2465.