Development of Novel Therapeutic Molecules for Treatment of Squamous Head and Neck Cancers

开发治疗鳞状头颈癌的新型治疗分子

基本信息

批准号：
10666868
负责人：
Judith S Leopold
金额：
$ 14.96万
依托单位：
MEKANISTIC THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10666868
关键词：
1-Phosphatidylinositol 3-Kinase ABCG2 gene Adverse event Animals Antineoplastic Agents Area Automobile Driving Biological Assay Biological Availability CYP1A2 gene CYP2B6 gene CYP2C19 gene CYP2C9 gene CYP2D6 gene CYP3A4 gene Cancer Model Cancer Prognosis Canis familiaris Cell Survival Clinic Clinical Clinical Trials Cyclic AMP-Dependent Protein Kinases Cytochrome P450 DNA Double Strand Break DNA Repair DNA Repair Enzymes DNA Repair Inhibition DNA Sequence Alteration DNA-dependent protein kinase Data Development Dose Drug Industry Drug Interactions Drug Kinetics Early identification Enzymes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Evaluable Disease Evaluation Event Exhibits Experimental Designs FRAP1 gene Family member Funding Future Goals Guidelines Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Human Implant In Vitro In complete remission Incidence Investigation Investigational Drugs Ion Channel Lead Left Maximum Tolerated Dose Measures Mediating Medical Modeling Monitor Mus Oncogenes Oncogenic POU2F1 gene POU2F2 gene Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Phosphatidylinositide 3-Kinase Inhibitor Phosphotransferases Pilot Projects Play Progression-Free Survivals Protein Isoforms Proto-Oncogene Proteins c-akt Public Health Publishing Radiation Radiation induced damage Radiation therapy Radiation-Sensitizing Agents Radiosensitization Rattus Recommendation Reporting Research Research Design Resistance Risk Role Route Safety Signal Transduction Signaling Molecule Solid Neoplasm Squamous cell carcinoma Survival Rate System Testing Therapeutic Therapeutic Index Time Toxic effect Tumor Burden United States Food and Drug Administration Xenograft procedure arm base design effective therapy follow-up head and neck cancer patient improved in vivo inhibitor irradiation mutant neoplastic cell novel novel therapeutics overexpression parent grant patient derived xenograft model patient population pre-clinical programs protein kinase inhibitor radiation resistance rational design receptor repaired response screening small molecule stem subcutaneous treatment strategy tumor tumor growth

项目摘要

Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively inhibit multiple oncogenic pathways. Among Mekanistic’s portfolio are dual and highly selective inhibitors of EGFR and PI3 kinase, which were rationally designed to only target these two critical oncogenes. The PI3 kinase (PI3K)/AKT/mTOR pathway plays a central role in driving tumor cell survival and progression. Despite intensive efforts of the pharmaceutical industry, PI3K inhibitors, encompassing isoform selective as well as pan-PI3K inhibitors, have largely failed to produce single agent activity against solid tumors. EGFR is a major contributor to the adaptive signaling mechanisms that lead to PI3K inhibitor resistance. Squamous cell carcinomas, which comprise an area of high unmet medical need, exhibit a high incidence of genomic alterations in both EGFR and PI3K. A central goal of this project is to provide preclinical proof of concept to support monotherapy development of a lead EGFR/PI3K inhibitor that is ideally suited to treat squamous head and neck cancers. Our preliminary data generated in multiple head and neck squamous cancer models strongly support this line of investigation. Phase I aims are focused on evaluation of the pre-lead molecule MTX-531 for its antitumor activity against patient-derived head and neck cancer xenografts in parallel with pharmacokinetic profiling in rats and dogs to assess bioavailability.

Mekanistic Therapeutics 致力于设计、发现和开发选择性的抗癌药物 Mekanistic 的产品组合包括双重且高度选择性的抑制剂。 EGFR 和 PI3 激酶，经过合理设计，仅针对这两个关键癌基因。 PI3 激酶 (PI3K)/AKT/mTOR 通路在驱动肿瘤细胞存活和进展中发挥着核心作用。尽管制药行业付出了巨大的努力，PI3K 抑制剂（包括异构体选择性）以及泛 PI3K 抑制剂，基本上未能产生针对实体瘤的单一药物活性。导致鳞状细胞 PI3K 抑制剂耐药的适应性信号传导机制的主要贡献者。癌症是一个医疗需求未得到满足的领域，具有很高的基因组发病率该项目的中心目标是提供临床前概念证明。支持主要 EGFR/PI3K 抑制剂的单一疗法开发，该抑制剂非常适合治疗鳞状头我们在多个头颈鳞状癌模型中生成的初步数据。强烈支持这一研究方向，第一阶段的目标是评估前先导分子。 MTX-531 对源自患者的头颈癌异种移植物具有抗肿瘤活性大鼠和狗的药代动力学分析以评估生物利用度。