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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：
10325253
负责人：
Judith S Leopold
金额：
$ 29.95万
依托单位：
MEKANISTIC THERAPEUTICS, LLC
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：
2021-09-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10325253
关键词：
1-Phosphatidylinositol 3-Kinase Antineoplastic Agents Area Assimilations Automobile Driving Binding Binding Sites Biological Availability Cancer Model Cancer Prognosis Canis familiaris Capital Cell Survival Cetuximab Chemistry Clinical Clinical Trials Combined Modality Therapy Computer Models DNA Sequence Alteration Data Deglutition Development Diagnosis Dose Drug Industry Drug Kinetics EGFR inhibition Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Evaluation Exhibits FDA approved FRAP1 gene Face Formulation Funding Future Goals Head Cancer Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure In Vitro Incidence Investigation Investments Lead Malignant Neoplasms Measures Medical Metabolic Molecular Mus Mutation Neck Cancer Oncogenes Oncogenic Oral Outcome PIK3CA gene PTEN gene Pathway interactions Patient Selection Patients Pharmacodynamics Pharmacologic Substance Phase Phosphatidylinositide 3-Kinase Inhibitor Phosphotransferases Play Program Development Protein Isoforms Proto-Oncogene Proteins c-akt Public Health Rattus Research Design Resistance Role Signal Transduction Signaling Molecule Small Business Technology Transfer Research Solid Neoplasm Solubility Squamous cell carcinoma Structure Survival Rate Therapeutic Toxicology Up-Regulation Xenograft Model Xenograft procedure alpelisib base candidate marker capsule clinical development commercial application comparative efficacy design effective therapy improved in vivo inhibitor/antagonist intravenous administration kinase inhibitor liquid formulation mutational status nanomolar neoplastic cell novel novel therapeutics oral HPV-positive head and neck cancers overexpression patient derived xenograft model phase 2 study pill pre-clinical resistance mechanism safety study single molecule small molecule success targeted treatment therapy development tumor

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抑制多种致癌途径。 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。这 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，在很大程度上未能产生针对实体瘤的单一药物活性。 EGFR是一种导致 PI3K 抑制剂耐药性的适应性信号传导机制的主要贡献者。鳞状细胞癌症是一个医疗需求未得到满足的领域，表现出基因组突变的高发病率 EGFR 和 PI3K 均发生改变。该项目的中心目标是提供临床前概念证明支持一种主要 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和颈部癌症。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调查路线。第一阶段的目标集中于评估前先导分子 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。