Development of a companion diagnostic to identify patients who respond to microbiome-targeting drugs

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The use of various classes of FDA-approved medicines, including non-steroidal anti-inflammatory drugs and anti- cancer drugs, is frequently associated with intestinal toxicities that can manifest as diarrhea, intestinal mucositis, ulceration, and bleeding. These serious and sometimes life-threatening side effects limit the treatment options for many patients. Often, intestinal toxicity is caused by the activity of the commensal bacteria (the microbiome) in the gut due to the activity of enzymes called beta-glucuronidases (GUS enzymes). Preclinical models demonstrate that specifically inactivating GUS enzymes alleviates the intestinal toxicities associated with some drugs. However, the human gut microbiome can include any combination of nearly 300 distinct GUS orthologs, making it very difficult to match an individual patient to a specific GUS inhibitor. The Stool GUS Activity (SGA) assay developed in Phase I has demonstrated feasibility in overcoming this barrier and has the potential to be developed into a validated companion diagnostic to match a patient to the best therapy. The SGA is a simple and rapid functional activity assay that evaluates GUS activity in stool samples isolated from patients. Thus, the SGA is an ex vivo approach to capture and inform in vivo activities and to assess interventional benefits of targeted GUS inhibitor drugs. Phase II studies are focused on developing an SGA kit for use as a clinical trial assay in future Phase 2 clinical trials. Research and development activities to be completed during Phase II include (1) defining the technical perfor- mance of the SGA in a healthy volunteer population; (2) replicating the technical performance of the SGA in the intended use population, metastatic colorectal and advanced pancreatic cancer patients undergoing treatment with the chemotherapeutic drug irinotecan; and (3) delivering a qualified SGA prototype kit ready for use as a clinical trial assay. Successful completion of the Aims of this proposal are expected to result in advancement of the SGA as a clinical trial assay in clinical studies of novel GUS inhibitor drugs.