Expanding the xenotopic toolbox for compartment-specific manipulation of redox stress in cancer

The National Cancer Institute awarded The Scintillon Institute $480,205 on June 1, 2026, under the Cancer Biology Research program (CFDA 93.396) to expand xenotopic tools for compartment-specific manipulation of redox stress in cancer cells. The award funds development of genetically encoded molecular tools that directly alter ratios of key redox coenzymes in a tissue- and organelle-specific manner, addressing a knowledge gap in understanding whether redox metabolism plays a causal role in cancer development and progression. Current approaches to targeting redox metabolism are limited by compartmentalization of redox coenzymes, moonlighting enzyme activities, presence of multiple isoforms, and lack of physiological relevance in cultured cells or xenograft models. The xenotopic approach avoids these caveats by introducing tools that systematically test the efficacy of promoting pro-reductive versus pro-oxidative shifts in metabolism across different cellular compartments in cancer, stromal, or immune cells. The work is performed in San Diego, California, with a period of performance from June 1, 2026, through May 31, 2028. The assistance type is a Project Grant (R21).

Abstract

Metabolic remodeling is a hallmark of cancer cells. Understanding metabolic rewiring in different types of malignant cells can be leveraged therapeutically by targeting these metabolic vulnerabilities. However, the lack of tools to directly assess the impact and temporal aspects of major components of redox metabolism limits our understanding of its role in cancer development and/or progression. Additionally, this dearth of available tools hinders our ability to distinguish whether redox metabolism plays a causal role or is simply a bystander in most cancer cells, representing a key knowledge GAP. Moreover, the lack of a methodology to systematically test the efficacy of promoting pro-reductive versus pro-oxidative shifts in metabolism prevents assessing the significance of these shifts in rewiring cancer biology. Targeting upstream, rate-limiting enzymes that regulate the redox state further complicates the interpretation of the significance of redox stress in cancer biology due to the high compartmentalization of redox coenzymes, the moonlighting activities of enzymes, the presence of multiple isoforms that alleviate the effects of single-enzyme perturbations, and, more importantly, the lack of physiological relevance when using cultured cells or xenograft models. One approach that avoids all these caveats is introducing xenotopic tools that directly alter the ratios of key redox coenzymes in a tissue- and organelle-specific manner. We and others have previously developed and validated several xenotopic tools in vivo that target various cancer-related metabolic pathways, including major redox coenzymes. Although some of these tools have been created as flox/flox models in mice, IT is not feasible to test all of them in different cellular compartments or in all possible combinations in cancer, stromal, or immune cells in mice. To address this, we have created an efficient solution by developing a drosophila model that allows US to monitor tumor growth and overall survival in a semi high-throughput manner. This proposal will further advance the creation and validation of organelle-specific versions of our tools and their systematic analysis in a drosophila cancer model to test the hypothesis that redox stress represents a metabolic vulnerability of cancer cells that can be exploited therapeutically. Our approach constitutes a substantial methodological advancement as IT will allow US to screen for multiple combinations of different redox states across various compartments and determine their significance in tumor growth in vivo. The proposed experiments will provide important mechanistic insights into the metabolic rewiring in cancer and a comprehensive inventory of compartmentalized redox pathways. Ultimately, this project will evaluate novel interventions that could target metabolic vulnerabilities in cancer cells and be employed as potential therapeutic strategies for the treatment of various cancers.