MT-125 for the Therapeutic Treatment of Glioblastoma

MT-125 用于胶质母细胞瘤的治疗

基本信息

批准号：
10697940
负责人：
STEVEN S ROSENFELD
金额：
$ 40.65万
依托单位：
MYOSIN THERAPEUTICS INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10697940
关键词：
Acceleration Adult Age Alleles Area Basic Science Biology Brain Brain Neoplasms Cell Proliferation Cells Chemotherapy and/or radiation Clinic Clinical Clinical Research Clinical Treatment Clinical Trials Combined Modality Therapy Consensus Country DNA Data Development Diagnosis Disease Doctor of Philosophy Dose Environment Excision FDA approved Formulation Future Genetic Engineering Glioblastoma Goals Guanine Heterogeneity In Vitro Incidence Industry Standard Invaded Investigational Therapies Isocitrate Dehydrogenase Laboratories Life Malignant Neoplasms Malignant neoplasm of brain Marketing Medical Modeling Molecular Motors Myosin ATPase Myosin Type II Nature Neurosciences Nonmuscle Myosin Type IIA Nonmuscle Myosin Type IIB Operative Surgical Procedures Pathogenesis Patients Penetrance Pharmaceutical Chemistry Pharmacologic Substance Phase Phenotype Polymorph Positioning Attribute Primary Brain Neoplasms Proliferating Radiation Radiation therapy Rattus Recurrence Research Research Personnel Resistance Resources Route Safety Signal Transduction Inhibitor Small Business Technology Transfer Research Solid Technology Therapeutic Time Transferase Validation Work chemotherapy clinical investigation commercialization curative treatments design drug development effective therapy efficacy testing gene therapy improved in vivo inhibitor innovation kinase inhibitor manufacturing scale-up mouse model neoplastic cell neuro-oncology non-muscle myosin novel strategies patient derived xenograft model pre-clinical preclinical efficacy preclinical study safety study screening small molecule small molecule inhibitor standard of care synergism temozolomide therapeutic target therapy resistant translational potential treatment response tumor

项目摘要

PROJECT SUMMARY An area of significant unmet need is the treatment of glioblastoma (GBM), an aggressive, fast-growing and lethal brain cancer that represents 48% of all malignant brain tumors. Untreated, GBM is fatal within three months, and due to its high rate of recurrence and invasive nature, the current standard of care, consisting of safe maximal tumor resection, radiation therapy and chemotherapy, only extends survival following initial diagnosis to one year. Invasion and proliferation, also known as Go and Grow, are defining phenotypes of GBM, and GBM cells do only one or the other. However, blocking invasion stimulates proliferation and vice versa, implying that an ideal therapeutic needs to block both Go and Grow simultaneously. Extensive genetic interventions have shown that simultaneous disruption of two non-muscle myosin II (NMII) molecular motors (NMIIA and IIB) meet these criteria. However, the translational potential of this research has been limited by the lack of a clinically safe, CNS-penetrant NMII small molecule inhibitor. Following extensive medicinal chemistry efforts to optimize selectivity for safety and tolerability, MT-125 was identified. MT-125 is a well-tolerated, dual small molecule inhibitor of NMIIA and IIB with a high degree of brain penetrance, a requirement for an effective GBM therapeutic. Preclinical in vitro and in vivo studies show that MT-125 blocks the Go and Grow phenotypes and extends survival. Due to its unique mode of action, MT-125 also synergizes with existing FDA-approved treatments, presenting a path to a potentially curative treatment. The overarching goal of the current proposal is to ready MT-125 for rapid entry into IND-enabling studies. This will be achieved through several activities. Phase I will focus on confirmation of preclinical efficacy with a clinically viable route of administration, in vitro studies of synergy between MT-125 and additional existing FDA-approved treatments, and in vitro safety profiling, pre-formulation studies and demo batch scale-up of MT-125. Quantitative milestones for transition to Phase II are detailed in the application. In Phase II, in vivo efficacy testing will be performed on the most promising synergy combinations identified in Phase I, as well as a non-GLP dosing safety study, GLP synthesis, and formulations development with polymorph screening. The Commercialization Plan details the GBM market, as well as Myosin Therapeutics’ clinical and regulatory strategy for rapid advancement of MT-125 to the clinic.

项目概要一个严重未满足需求的领域是胶质母细胞瘤 (GBM) 的治疗，这是一种侵袭性、快速生长的疾病致命性脑癌占所有恶性脑肿瘤的 48%，未经治疗，GBM 会在 3 年内致命。几个月，并且由于其高复发率和侵入性，目前的护理标准包括安全的最大肿瘤切除术、放射治疗和化疗，仅在初始治疗后延长生存期诊断到一年内的侵袭和增殖，也称为“Go”和“Grow”，是 GBM 的表型。 GBM 细胞只执行其中之一，然而，阻止侵袭会刺激增殖，反之亦然。这意味着理想的治疗方法需要同时阻断 Go 和 Grow 基因。干预措施表明，同时破坏两个非肌肉肌球蛋白 II (NMII) 分子马达（NMIIA 和 IIB）符合这些标准，但是这项研究的转化潜力受到了限制。经过广泛的药物化学研究，缺乏临床安全的、中枢神经系统渗透性的 NMII 小分子抑制剂。为了优化安全性和耐受性的选择性，MT-125 被确定为一种耐受性良好的双重药物。 NMIIA 和 IIB 的小分子抑制剂，具有高度的脑渗透性，这是有效治疗的必要条件 GBM 治疗。临床前体外和体内研究表明 MT-125 可阻断 Go 和 Grow 表型。由于其独特的作用方式，MT-125 还可以与 FDA 批准的现有药物产生协同作用。治疗，提出了一条潜在的治疗方法当前提案的总体目标。准备 MT-125 快速进入 IND 支持研究，这将通过多项活动来实现。第一阶段将侧重于通过临床上可行的体外给药途径确认临床前疗效 MT-125 与 FDA 批准的其他现有疗法之间的协同作用以及体外安全性研究 MT-125 的分析、预配方研究和演示批量放大。过渡到的定量里程碑。第二阶段在申请中进行了详细说明。第二阶段将在大多数情况下进行体内功效测试。第一阶段确定的有前景的协同组合，以及非 GLP 剂量安全研究、GLP 合成、商业化计划详细介绍了 GBM 市场，以及 Myosin Therapeutics 为将 MT-125 快速推向临床而制定的临床和监管策略。