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

开发伴随诊断来识别对微生物组靶向药物有反应的患者

基本信息

批准号：
10207667
负责人：
Bret David Wallace
金额：
$ 84.67万
依托单位：
SYMBERIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207667
关键词：
Antineoplastic Agents Award Bacterial Genes Beta-glucuronidase Biological Assay Buffers Camptothecin Cancer Patient Catabolism Chemicals Clinical Research Clinical Trials Colorectal Companions Comprehensive Cancer Center Data Development Devices Diagnostic Diarrhea Disease Dose Drug Targeting Ensure Enzymes Escherichia coli Evaluation FDA approved Feces Feedback Future Glucuronidase Inhibitor Glucuronides Glucuronosyltransferase Goals Hemorrhage Human Human Microbiome Individual Intervention Intestines Investigation Lead Life Liver Lower Gastrointestinal Tract Medicine Metagenomics Monitor Mucositis Mycophenolate National Institute of Diabetes and Digestive and Kidney Diseases National Institute of General Medical Sciences Non-Steroidal Anti-Inflammatory Agents North Carolina Orthologous Gene Patient Schedules Patients Performance Pharmaceutical Preparations Phase Phase II Clinical Trials Poison Population Pre-Clinical Model Preparation Prevention Procedures Process Production Proteins Publishing Regimen Reproducibility SN-38 SN-38G Sampling Small Business Innovation Research Grant Specificity Standardization Structure Temperature Testing Therapeutic Therapeutic Studies Therapeutic Trials Toxic effect Tyrosine Kinase Inhibitor Ulcer Universities Work advanced pancreatic cancer base cancer type chemotherapeutic agent chemotherapy commensal bacteria companion diagnostics deep sequencing effectiveness evaluation enzyme activity gut bacteria gut microbiome gut microbiota healthy volunteer human data in vivo individual patient inter-individual variation irinotecan lead candidate metastatic colorectal microbiome microbiota novel pancreatic cancer patients patient response patient subsets phase 2 study pre-clinical precision medicine predictive test programs prospective prototype research and development scaffold side effect small molecule small molecule inhibitor sound standard of care stool sample targeted treatment transcriptomics

项目摘要

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.

使用各种FDA批准的药物，包括非甾体类抗炎药和抗抗药性药物癌症药物经常与肠道毒性相关，这些毒性可能表现为腹泻，肠粘膜炎，溃疡和流血。这些严重的，有时威胁生命的副作用限制了许多患者。通常，肠道毒性是由共生细菌（微生物组）在肠道由于酶的活性称为β-葡萄糖醛酸苷（GUS酶）。临床前模型证明了特别灭活的GUS酶可以减轻与某些药物相关的肠道毒性。然而，人类肠道微生物组可以包括近300个不同的GUS直系同源物的任何组合，使其非常困难将个体患者与特定的GUS抑制剂相匹配。粪便GUS活性（SGA）分析在相时开发我已经证明了克服这一障碍的可行性，并有可能发展为经过验证的伴侣诊断将患者与最佳疗法相匹配。 SGA是一种简单而快速的功能活动评估从患者分离的粪便样品中的GUS活性的测定。因此，SGA是一种离体方法捕获和告知体内活动并评估目标GUS抑制剂药物的介入益处。阶段 II研究的重点是开发SGA套件，以用作未来2期临床试验的临床试验测定。在第二阶段期间要完成的研发活动包括（1）定义技术性能在健康的志愿者人口中，SGA的曼斯；（2）复制SGA的技术性能预期使用人群，转移性结直肠癌和晚期胰腺癌患者接受治疗化学治疗药物伊立替康；（3）提供合格的SGA原型套件，准备用作临床试验测定。预计成功完成该提案的目标将导致SGA的进步作为新型GUS抑制剂药物临床研究的临床试验测定。