Abstract IA01: Molecular control of the gut microbiome to improve cancer chemotherapy

Abstract

Abstract The diverse and complex communities of GI microbiota play important roles in human health, particularly with respect to cancer chemotherapy. We focused on systems where gut bacteria catalyze reactions that exert a profoundly negative impact on intestinal tissues and prove to be dose limiting for chemotherapy. The anticancer drug irinotecan is used to treat colon and pancreatic cancers and is eliminated as an inactivated drug-glucuronide by the phase II drug metabolism. Irinotecan’s dose-limiting toxicity is severe delayed diarrhea hypothesized to arise from the reactivation of the inactive irinotecan metabolite in the gut. We pinpointed the molecular basis of this reactivation to the beta-glucuronidase sugar-scavenging enzymes present in gut bacteria. We further developed potent, selective, and nonlethal inhibitors to bacterial beta-glucuronidase (GUS) enzymes and demonstrated that they prevented GI injury in mouse models of irinotecan-induced intestinal damage. Bacterial GUS inhibitors also prevent these sites of intestinal damage in mice treated with NSAIDs, which are glucuronidated and used to control cancer-related inflammation. We have since extended this work to the tyrosine kinase inhibitor regorafenib and to a probe-enabled activity-based proteomics pipeline to discover the enzymes driving the production of toxic metabolites. Together, our data demonstrate that enzyme targets in the GI microbiota can be inhibited to improve cancer care in a manner that can advance the promise of personalized medicine. Furthermore, our results shed significant light on the mammalian-microbial axes of chemical communication ongoing between two domains of life in the “higher-order” human superorganism. Citation Format: Matthew Redinbo. Molecular control of the gut microbiome to improve cancer chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr IA01.