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.

项目概要针对癌症治疗的单一致癌途径是可行的，但通常不是很有效，因为患者反应是短暂的，受到毒性的阻碍，并且总是被进行性疾病所取代。替代策略是针对全球癌症网络，这有望禁用多种机制。肿瘤立即生长，避免耐药性的出现，对不同的疾病有效恶性肿瘤，无论遗传或分子异质性如何。热休克蛋白 90 (Hsp90) 池线粒体 Hsp90 是这样的癌症网络之一。与正常组织相比，在癌症中过度表达，通过以下方式支持肿瘤生长的多种机制出乎意料的是，这种途径可能会导致临床上更糟糕的疾病结果。不能作为药理学目标，因为迄今为止开发的 Hsp90 拮抗剂均不具备为此，我们开发了加米替尼（GA 线粒体基质抑制剂）。一流的线粒体靶向小分子 Hsp90 抑制剂，具有独特的组合结构，加米替尼选择性地在线粒体中积累，破坏细胞器蛋白质折叠环境，并且关闭肿瘤生长所需的生物能、代谢和细胞存活的多种途径。反过来，这转化为针对异质肿瘤的有效细胞毒活性，作为单一疗法或在异种移植和转基因疾病中原发性和转移性肿瘤生长的组合和抑制仅通过公共资助推进，Gamitrinib 的临床前开发现已完成。 (PIND #132453)，显示出有利的类似药物的特性，鼓励两种动物的安全性，以及 “细胞饥饿”的独特特征作为体内靶标抑制的生物标志物因此，该假设。 Gamitrinib 提供了第一个针对线粒体的亚细胞定向癌症疗法可以制定肿瘤维持网络，并将构成本申请的焦点。第一个具体目标将支持每周静脉输注的首次人体 I 期临床试验这些研究将确定加米替尼在晚期癌症患者中的最大耐受剂量（MTD）。使用加速剂量递增的加米替尼的剂量限制毒性 (DLT) 和药代动力学 MTD 扩展队列的方案第二个具体目标是表征药物的药效学。加米替尼在治疗前和治疗后的肿瘤活检和外周血单核细胞中的应用这些研究将描述加米替尼治疗的代谢缺陷和评估“细胞饥饿”特征，包括抑制 AMPK 信号传导、诱导自噬、总体而言，该提案旨在实现蛋白毒性应激的调节和 mTOR 信号传导的抑制。向诊所提供一种新型抗癌剂，具有独特的作用机制和广泛的“肿瘤不可知”功效。