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

使用各种类别的FDA批准的药物，包括非甾体抗炎药和抗 癌症药物，通常与肠道毒性有关，可表现为腹泻，肠粘膜炎， 溃疡和出血这些严重的，有时危及生命的副作用限制了治疗选择， 很多病人。通常，肠道毒性是由肠道中的肠道细菌（微生物组）的活性引起的。 由于称为β-葡萄糖醛酸酶（GUS酶）的酶的活性，临床前模型证明 特异性失活GUS酶可消除某些药物引起的肠道毒性。但是，在这方面， 人类肠道微生物组可以包括近300种不同GUS直向同源物的任何组合，这使得很难 来将个体患者与特定的GUS抑制剂相匹配。粪便GUS活性（SGA）测定法在第二期开发， 我已经证明了克服这一障碍的可行性，并有可能发展成为一个经过验证的 伴随诊断，为患者匹配最佳治疗。SGA是一种简单快速的功能性活动， 本发明提供了一种评估从患者分离的粪便样品中的GUS活性的测定。因此，SGA是一种离体方法 以捕获和告知体内活性并评估靶向GUS抑制剂药物的干预益处。相 II期研究的重点是开发一种SGA试剂盒，用作未来II期临床试验的临床试验测定。 在第二阶段完成的研究和开发活动包括：（1）确定技术性能; SGA在健康志愿者群体中的管理;（2）在健康志愿者群体中复制SGA的技术性能。 预期用途人群，接受以下治疗的转移性结直肠癌和晚期胰腺癌患者 化疗药物伊立替康;和（3）提供合格的SGA原型试剂盒，准备用作临床治疗药物。 试验测定成功完成本提案的目标有望推动SGA的发展 作为新型GUS抑制剂药物临床研究中的临床试验测定。

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.