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：
9668658
负责人：
Dario C Altieri
金额：
$ 41.03万
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/9668658
关键词：
Advanced Malignant Neoplasm Advanced Malignant Neoplasm Aftercare Aftercare Animals Animals Antineoplastic Agents Antineoplastic Agents Autophagocytosis Autophagocytosis Biochemical Biochemical Bioenergetics Bioenergetics Biological Markers Biological Markers Biopsy Biopsy Cell Survival Cell Survival Clinic Clinic Clinical Protocols Clinical Protocols Clinical Research Clinical Research Data Data Defect Defect Developmental Therapeutics Program Developmental Therapeutics Program Disease Outcome Disease Outcome Disease model Disease model Doctor of Medicine Doctor of Medicine Dose Dose Dose-Limiting Dose-Limiting Drug Kinetics Drug Kinetics Drug resistance Drug resistance Environment Environment Evaluation Evaluation FRAP1 gene FRAP1 gene Fox Chase Cancer Center Fox Chase Cancer Center Funding Funding Genetic Genetic Goals Goals Harvest Harvest Heat-Shock Proteins 90 Heat-Shock Proteins 90 Heterogeneity Heterogeneity Immunohistochemistry Immunohistochemistry Institution Institution Intravenous infusion procedures Intravenous infusion procedures Link Link Maintenance Maintenance Malignant Neoplasms Malignant Neoplasms Maximum Tolerated Dose Maximum Tolerated Dose Metabolic Pathway Metabolic Pathway Metabolism Metabolism Mitochondria Mitochondria Mitochondrial Matrix Mitochondrial Matrix Molecular Molecular Molecular Chaperones Molecular Chaperones Monitor Monitor Neoplasm Metastasis Neoplasm Metastasis Normal tissue morphology Normal tissue morphology Oncogenes Oncogenes Oncogenic Oncogenic Organelles Organelles Pathway interactions Pathway interactions Patients Patients Peripheral Blood Mononuclear Cell Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Pharmaceutical Preparations Pharmacodynamics Pharmacodynamics Pharmacology Pharmacology Phase Phase Phase I Clinical Trials Phase I Clinical Trials Phosphorylation Phosphorylation Primary Neoplasm Primary Neoplasm Principal Investigator Principal Investigator Progressive Disease Progressive Disease Property Property Proteins Proteins Protocols documentation Protocols documentation Safety Safety Scheme Scheme Signal Induction Signal Induction Signal Transduction Signal Transduction Starvation Starvation Stress Stress Structure Structure Surrogate Markers Surrogate Markers Titrations Titrations Toxic effect Toxic effect Transgenic Organisms Transgenic Organisms Translating Translating Western Blotting Western Blotting Xenograft procedure Xenograft procedure anticancer activity anticancer activity cancer therapy cancer therapy clinical infrastructure clinical infrastructure cohort cohort combinatorial combinatorial cytotoxic cytotoxic design design first-in-human first-in-human in vivo in vivo inhibitor/antagonist inhibitor/antagonist intravenous administration intravenous administration metabolic profile metabolic profile novel novel novel anticancer drug novel anticancer drug open label open label overexpression overexpression patient response patient response preclinical development preclinical development programs programs protein folding protein folding proteotoxicity proteotoxicity response response small molecule small molecule targeted agent targeted agent targeted biomarker targeted biomarker targeted cancer therapy targeted cancer therapy tumor tumor tumor growth tumor growth week trial 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.

项目摘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，并总是被进行性疾病所取代。一个替代策略是针对全球癌症网络。预计这将禁用多种机制肿瘤生长一次，避免耐药性的出现并有效恶性，无论遗传或分子异质性如何。热休克蛋白-90（HSP90）线粒体局部的伴侣策划了一个这样的癌症网络。线粒体HSP90是与正常组织相比，在癌症中过表达的癌症，支持多种肿瘤生长的机制蛋白质折叠的增强，并在诊所赋予较差的疾病预后。出乎意料的是，这条路可能不是针对药物的，因为到目前为止，HSP90拮抗剂都没有能力积聚在线粒体中。因此，我们开发了gamitrinib（GA线粒体基质抑制剂），一类，线粒体靶向小分子HSP90抑制剂。具有独特的组合结构， gamitrinib有选择地积累线粒体，破坏细胞器蛋白质折叠环境，并关闭了肿瘤生长所需的生物能学，代谢和细胞存活的多种途径。在转弯，这翻译了针对异质肿瘤的有效细胞毒性活性，作为单一疗法或异种移植物和转基因疾病中原发性和转移性肿瘤生长的结合以及抑制型号。仅通过公共资金提高，Gamitrinib的临床前发展现已完成（Pind＃132453），显示出有利的毒品样特性，鼓励两种动物物种的安全性，A 体内的“细胞饥饿”作为靶抑制的生物标志物的独特特征。因此，假设 Gamitrinib提供了第一个针对线粒体的亚细胞癌疗法可以制定肿瘤维持网络，并构成本应用的重点。第一个特定目的将支持每周静脉输注的第一阶段临床试验 Gamitrinib患有晚期癌症患者。这些研究将确定最大耐受剂量（MTD），剂量限制毒性（DLT）和Gamitrinib的药代动力学使用加速剂量升级在MTD处具有扩展队列的协议。第二个特定目的将表征在治疗前和治疗后肿瘤活检中的gamitrinib和从从中收获的外周血单核细胞患者扩张队列。这些研究将介绍Gamitrinib疗法的代谢缺陷和评估AMPK信号传导的“细胞饥饿”签名抑制，自噬的诱导，蛋白质毒性应激的调节和MTOR信号传导的抑制。总体而言，该提案旨在带来向诊所致以一种新型的抗癌剂，具有独特的作用机理和广泛的“肿瘤无关”有效性。