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旨在设计，发现和开发有选择地的抗癌药抑制多个致癌途径。在Mekanistic的投资组合中，有双重和高度选择性的抑制剂 EGFR和PI3激酶的理性设计仅针对这两种关键的癌基因。这 PI3激酶（PI3K）/AKT/MTOR途径在驱动肿瘤细胞的存活和进展中起着核心作用。尽管制药行业进行了密集的努力，但PI3K抑制剂，涵盖了同工型的选择性以及PAN-PI3K抑制剂，在很大程度上未能针对实体瘤产生单一药物活性。 egfr是一个导致PI3K抑制剂耐药性的自适应信号传导机制的主要贡献者。鳞状细胞癌完成了高未满足医疗需求的癌症，暴露了一系列基因组事件 EGFR和PI3K的改变。该项目的核心目标是向临床前的概念证明支持铅EGFR/PI3K抑制剂的单一治疗开发，非常适合治疗鳞状头和脖子癌。我们在多个头颈鳞癌模型中生成的初步数据强烈支持这一投资线。第一阶段的目的是评估前铅分子 MTX-531的抗肿瘤活性与患者衍生的头颈癌异种移植与同行大鼠和狗的药代动力学分析，以评估生物利用度。