Selection and preclinical development of a bacteria-targeting, non-antibiotic lead candidate to improve cancer chemotherapy outcomes

选择和临床前开发一种针对细菌的非抗生素主要候选药物，以改善癌症化疗结果

• 批准号: 10006516
• 负责人: Ward Peterson
• 金额: $ 99.95万
• 依托单位: SYMBERIX, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006516
• 关键词: Acute; Antibiotics; Antineoplastic Agents; Back; Bacteria; Beta-glucuronidase; Binding Proteins; Camptothecin; Cancer Patient; Canis familiaris; Caring; Chemistry; Chemotherapy-Oncologic Procedure; Clinical Trials; Collaborations; Colorectal Cancer; Data; Development; Diarrhea; Dose; Drug Kinetics; Drug usage; Effectiveness; Enterobacteriaceae; Enterocytes; Enzyme Inhibitor Drugs; Enzymes; Evaluation; Event; Genetic; Glucuronides; Goals; Hospitalization; In Vitro; Incidence; Investigational Drugs; Investigational New Drug Application; Lead; Liver; Lower Gastrointestinal Tract; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measures; Medical; Medicine; Metabolism; Methods; Modification; Molecular; Mus; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Pharmacology Study; Phase; Plasma; Plasma Proteins; Population; Preparation; Prevention; Quality of life; Reporting; Risk; Rodent; Safety; Small Business Innovation Research Grant; System; Therapeutic; Topoisomerase-I Inhibitor; Toxicity Tests; Toxicokinetics; Toxicology; Treatment outcome; Work; analog; analytical method; base; chemotherapeutic agent; chemotherapy; cytotoxicity; drug discovery; experience; first-in-human; gut bacteria; gut microbiome; improved; in vitro testing; in vivo; irinotecan; lead candidate; meetings; microbiome; novel; palliative; pancreatic cancer patients; phase 2 study; phase 2 testing; plasma lead level; pre-clinical; preclinical development; preclinical safety; preclinical study; preclinical toxicity; prevent; small molecule inhibitor; sugar; survival outcome; targeted treatment; therapeutic effectiveness

The long-term objective of this project is a therapeutic adjunct to prevent chemotherapy-induced diarrhea (CID) based on a completely new mechanism of action targeting enteric bacteria. This Fast-Track SBIR proposal outlines the strategy for selecting a lead development candidate to be evaluated in investigational new drug (IND)-enabling studies to support a first-in-human trial. The focus of this project is prevention of diarrhea associated with irinotecan (IRI), an important drug used to treat advanced colorectal and pancreatic cancer patients. Intense, delayed diarrhea is the major reason for reducing, postponing or stopping IRI chemotherapy. The cancer-killing, active agent of IRI is SN38, a potent topoisomerase I inhibitor. As part of its elimination from the body, SN38 is detoxified primarily by the liver to an inactive glucuronide (SN38-G) that is subsequently shuttled to the lower gastrointestinal tract. The β-glucuronidase enzyme (GUS) expressed in a subset of gut bacteria metabolizes SN38-G back into SN38, which is highly toxic to enterocytes. This reactivation of SN38 by bacterial GUS in the gut microbiome is a key triggering event leading ultimately to serious, delayed diarrhea. A selective, non-proprietary bacterial GUS inhibitor (SBX-1) was previously shown to alleviate IRI-induced diarrhea in rodents. Phase 1 of this project discloses five proprietary analogs of SBX-1 and outlines the efficacy/tolerability studies to enable selection of the two most promising analogs to advance into Phase 2 SBIR studies. The lead candidate will be selected in the first aim of Phase 2. The remaining Phase 2 activities include chemistry/manufacturing/control (CMC)-related work and regulatory/safety preclinical studies that will transition this project from drug discovery to preclinical development. Aim 1 (Phase 1): Profile novel SBX-1 analogs in vitro for their off-target pharmacology, cytotoxicity, metabolism liability and stability in plasma. Aim 2 (Phase 1): Identify the two most promising SBX-1 analogs based on their therapeutic window and candidacy for formal preclinical studies. Aim 3 (Phase 2): Select lead candidate. Generate CMC and additional non-GLP preclinical data to support a pre-IND meeting with the FDA. Aim 4 (Phase 2): Conduct CMC-related activities to enable formal evaluations of the formulated lead candidate in GLP toxicology and safety pharmacology studies. A key deliverable in the proposed Phase 2 work is a preclinical data package that will adequately qualify the lead candidate for further evaluation in an acute-administration, first-in-human clinical trial in advanced colorectal and/or pancreatic cancer patients undergoing irinotecan-containing chemotherapy.

该项目的长期目标是预防化疗性腹泻（CID）的辅助治疗。