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A First-in-Human Phase I Clinical Trial of Mitochondrial-Targeted Hsp90 Inhibitor, Gamitrinib

线粒体靶向 Hsp90 抑制剂 Gamitrinib 的首次人体 I 期临床试验

基本信息

批准号：
10472429
负责人：
Dario C Altieri
金额：
$ 31.63万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472429
关键词：
Advanced Malignant Neoplasm Aftercare Animals Antineoplastic Agents Autophagocytosis Biochemical Bioenergetics Biological Markers Biopsy Cell Survival Clinic Clinical Protocols Clinical Research Data Defect Developmental Therapeutics Program Disease Outcome Disease model Doctor of Medicine Dose Dose-Limiting Drug Kinetics Drug resistance Environment Evaluation FRAP1 gene Fox Chase Cancer Center Funding Genetic Goals Harvest Heat-Shock Proteins 90 Heterogeneity Immunohistochemistry Institution Intravenous infusion procedures Link Maintenance Malignant Neoplasms Maximum Tolerated Dose Metabolic Pathway Metabolism Mitochondria Mitochondrial Matrix Molecular Molecular Chaperones Monitor Neoplasm Metastasis Normal tissue morphology Oncogenes Oncogenic Organelles Pathway interactions Patients Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Phase I Clinical Trials Phosphorylation Primary Neoplasm Principal Investigator Progressive Disease Property Proteins Protocols documentation Safety Scheme Signal Induction Signal Transduction Starvation Stress Structure Surrogate Markers Titrations Toxic effect Transgenic Organisms Translating Western Blotting Xenograft procedure antagonist anticancer activity cancer therapy clinical infrastructure cohort combinatorial cytotoxic design first-in-human in vivo inhibitor intravenous administration metabolic profile novel novel anticancer drug open label overexpression patient response preclinical development programs protein folding proteotoxicity response small molecule targeted agent targeted biomarker targeted cancer therapy tumor tumor growth week trial

项目摘要

PROJECT SUMMARY Targeting a single oncogenic pathway for cancer therapy is feasible but generally not very effective, as patient responses are short-lived, hampered by toxicity and invariably supplanted by progressive disease. An alternative strategy is to target global cancer networks. This is expected to disable multiple mechanisms of tumor growth at once, circumvent the emergence of drug resistance and be effective in disparate malignancies, regardless of genetic or molecular heterogeneity. A pool of Heat Shock Protein-90 (Hsp90) chaperones localized in mitochondria orchestrates one such cancer network. Mitochondrial Hsp90s are overexpressed in cancer, compared to normal tissues, support multiple mechanisms of tumor growth through heightened protein folding, and confer worse disease outcome in the clinic. Unexpectedly, this pathway could not be targeted pharmacologically, as none of the Hsp90 antagonists developed so far has the ability to accumulate in mitochondria. For this reason, we developed Gamitrinib (GA mitochondrial matrix inhibitor), the first-in-class, mitochondrial-targeted, small molecule Hsp90 inhibitor. With a unique combinatorial structure, Gamitrinib selectively accumulates in mitochondria, disrupts the organelle protein folding environment, and shuts down multiple pathways of bioenergetics, metabolism, and cell survival required for tumor growth. In turn, this translates in potent cytotoxic activity against heterogeneous tumors as monotherapy or in combination, and inhibition of primary and metastatic tumor growth in xenograft and transgenic disease models. Advanced solely through public funding, the preclinical development of Gamitrinib is now complete (PIND #132453), showing favorable drug-like properties, encouraging safety in two animal species, and a unique signature of “cellular starvation” as biomarker of target inhibition, in vivo. Therefore, the hypothesis that Gamitrinib provides the first subcellularly-directed cancer therapy targeting a mitochondrial network of tumor maintenance can be formulated, and will constitute the focus of the present application. The first specific aim will support a first-in-human, phase I clinical trial of weekly intravenous infusion of Gamitrinib in patients with advanced cancer. These studies will determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacokinetics of Gamitrinib using an accelerated dose-escalation protocol with expansion cohort at MTD. The second specific aim will characterize the pharmacodynamics of Gamitrinib in pre- and post-treatment tumor biopsies and peripheral blood mononuclear cells harvested from the patient expansion cohort. These studies will profile the metabolic defects of Gamitrinib therapy and evaluate a “cellular starvation” signature comprising inhibition of AMPK signaling, induction of autophagy, modulation of proteotoxic stress and suppression of mTOR signaling. Overall, the proposal is designed to bring to the clinic a novel anticancer agent with a unique mechanism of action and broad, “tumor-agnostic” efficacy.

项目总结