Developing novel inhibitors of the gut microbiome to modulate drug metabolism

The long-term objective of this project is a therapeutic adjunct to prevent adverse gastrointestinal events, including life-threatening diarrhea, associated with Ofev® and Stivarga®, used to treat idiopathic pulmonary fibrosis and metastatic colorectal cancer, respectively. Adverse GI events associated with both drugs is a major reason for reducing, postponing, or stopping treatment, thus compromising efficacy. One fundamental and common source of drug-dependent lower GI adverse events is microbiome-mediated drug metabolism, during which commensal β-glucuronidase enzymes (GUS) reactivate drug metabolites in the gut. We previously demonstrated the therapeutic efficacy of GUS enzyme inhibition as a novel “Symbiotic Drug” approach to ameliorate gastrointestinal sequela associated with common anti-inflammatory drugs and the chemotherapeutic agent, irinotecan. Here, we aim to identify novel symbiotic drugs to increase the efficacy of Ofev and Stivarga, while simultaneously reducing the risk of side effects. We previously developed a rapid screening assay that uses a clinically relevant source of GUS enzymes, and demonstrated that Ofev and Stivarga metabolites are substrates for bacterial GUS enzymes. In Phase I we will optimize our assay for high-throughput screening for novel GUS inhibitors. In Phase II, we will commence a high-throughput screen, identify lead candidate GUS inhibitors, and define the symbiotic drug candidacy of each. A key deliverable in the proposed project is a lead drug series for both Ofev and Stivarga, which will be evaluated for efficacy and safety in future pre-clinical animal studies. We expect that the development and validation of a comprehensive class of GUS inhibitors will be broadly applicable to improve the therapeutic index of many existing drugs.This project aims to discover and develop microbiome targeting therapeutics that selectively block the activity of a bacterial enzyme responsible for triggering the debilitating and sometimes deadly diarrhea that can occur in patients using Ofev®, used to treat idiopathic pulmonary fibrosis, and Stivarga®, used to treat metastatic colorectal cancer. This project builds on a unique microbiome-targeted approach to enhance the quality of life of patients using these drugs.