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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：
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.

机械疗法旨在设计，发现和开发选择性地抑制多种致癌途径。在Mekanistic的产品组合中， EGFR和PI 3激酶，其被合理地设计为仅靶向这两个关键癌基因。的 PI 3激酶（PI 3 K）/AKT/mTOR通路在驱动肿瘤细胞存活和进展中起核心作用。尽管制药工业进行了大量的努力，但PI 3 K抑制剂，包括选择性作为以及pan-PI 3 K抑制剂在很大程度上不能产生针对实体瘤的单一药剂活性。EGFR是是导致PI 3 K抑制剂抗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高度未满足医疗需求的领域， EGFR和PI 3 K的改变。该项目的中心目标是提供临床前概念验证，支持开发一种理想地适合治疗鳞状上皮细胞癌头部的主要EGFR/PI 3 K抑制剂的单一疗法和颈部癌症。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调查方向。第一阶段的目标是集中在评价前铅分子 MTX-531对患者来源的头颈癌异种移植物的抗肿瘤活性与MTX-531对患者来源的头颈癌异种移植物的抗肿瘤活性平行。在大鼠和狗中进行药代动力学分析以评估生物利用度。