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。