Development of MTX-211 for the Treatment of KRAS Mutant Colorectal Cancer

开发用于治疗 KRAS 突变结直肠癌的 MTX-211

基本信息

批准号：
9891971
负责人：
Judith S Leopold
金额：
$ 97.3万
依托单位：
MEKANISTIC THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891971
关键词：
1-Phosphatidylinositol 3-Kinase Achievement Advanced Development Antineoplastic Agents Cancer Model Cancer Prognosis Capital Chemistry Chemotherapy-Oncologic Procedure Clinical Collaborations Colorectal Cancer Combined Modality Therapy Data Development Diagnosis Disease Dose Epidermal Growth Factor Receptor Evaluation Fluorouracil Funding Future Immunotherapy In Vitro Investments KRAS2 gene Laboratories Lead MAP Kinase Gene MEK inhibition MEKs Maximum Tolerated Dose Michigan Mismatch Repair Mitogen-Activated Protein Kinases Modeling Molecular Profiling Molecular Target Mus Mutation Oncogenic Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phosphotransferases Play Population Process Production Prognostic Marker Public Health Risk Role Safety Signal Transduction Signaling Molecule Small Business Innovation Research Grant Survival Rate Testing Therapeutic Time Toxicology Universities Up-Regulation Xenograft Model active control base candidate marker clinical development colon cancer patients colorectal cancer treatment commercial application design early phase clinical trial effective therapy efficacy trial follow-up improved improved outcome inhibitor/antagonist interest lead candidate metastatic colorectal mutant novel phase 2 study pre-clinical preclinical study resistance mechanism response response biomarker safety study scale up single molecule targeted agent therapy development therapy outcome trial design tumor

1-Phosphatidylinositol 3-Kinase Achievement Advanced Development Antineoplastic Agents Cancer Model Cancer Prognosis Capital Chemistry Chemotherapy-Oncologic Procedure Clinical Collaborations Colorectal Cancer Combined Modality Therapy Data Development Diagnosis Disease Dose Epidermal Growth Factor Receptor Evaluation Fluorouracil Funding Future Immunotherapy In Vitro Investments KRAS2 gene Laboratories Lead MAP Kinase Gene MEK inhibition MEKs Maximum Tolerated Dose Michigan Mismatch Repair Mitogen-Activated Protein Kinases Modeling Molecular Profiling Molecular Target Mus Mutation Oncogenic Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phosphotransferases Play Population Process Production Prognostic Marker Public Health Risk Role Safety Signal Transduction Signaling Molecule Small Business Innovation Research Grant Survival Rate Testing Therapeutic Time Toxicology Universities Up-Regulation Xenograft Model active control base candidate marker clinical development colon cancer patients colorectal cancer treatment commercial application design early phase clinical trial effective therapy efficacy trial follow-up improved improved outcome inhibitor/antagonist interest lead candidate metastatic colorectal mutant novel phase 2 study pre-clinical preclinical study resistance mechanism response response biomarker safety study scale up single molecule targeted agent therapy development therapy outcome trial design tumor

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项目摘要

PROJECT SUMMARY Mekanistic Therapeutics seeks to design, discover, and develop anti-cancer agents that selectively inhibit multiple oncogenic pathways. Its lead agent MTX-211 was discovered in collaboration with the Leopold laboratory at University of Michigan. The overall objective of this project is to expediently advance MTX- 211 into development for the treatment of KRAS mutant colorectal cancer (CRC). Every year >130,000 new patients are diagnosed with colorectal cancer. At the time of diagnosis, approximately 20% of these patients present with metastatic disease. Currently, there are no approved treatments for metastatic CRC patients with activating mutations in KRAS. MTX-211 is a first-in-class highly selective dual inhibitor of PI3K and EGFR kinases, designed to attack KRAS oncogenic signaling using two orthogonal mechanisms. As such, it embodies a combination approach in a single molecule. Phase I aims focused on optimizing the synthetic process to scale-up production of MTX-211 and conducting a pilot mouse trial of primary xenograft models established from six different patients diagnosed with KRAS mutant CRC. All milestones were achieved providing preclinical proof-of-concept for pursuit of a clinical development path for MTX-211 that specifically targets the KRAS mutant CRC population. In Phase II, we propose to test a broader panel of KRAS mutant CRC models in an expanded efficacy trial that incorporates molecular profiling to identify prognostic markers that correlate with therapeutic outcome. At the same time, we propose to carry out early safety studies to further de-risk MTX-211 and strengthen the case for moving forward to future IND-enabling toxicology studies.

项目摘要 Mekanistic Therapeutics旨在设计，发现和开发有选择地抑制的抗癌药多个致癌途径。它的主要代理MTX-211与Leopold合作发现了密歇根大学实验室。该项目的总体目的是方便推进MTX- 211用于治疗KRAS突变结肠癌（CRC）的发展。每年> 130,000 新患者被诊断为结直肠癌。在诊断时，其中约有20％患者出现转移性疾病。目前，没有批准的转移治疗方法 CRC患者在KRAS中激活突变。 MTX-211是一流的高度选择性双抑制剂 PI3K和EGFR激酶的作品，旨在使用两个正交攻击KRAS致癌信号传导机制。因此，它体现了单个分子中的组合方法。 I阶段的目标优化合成过程以扩展MTX-211的生产并进行试验小鼠由六个不同患者诊断为KRAS突变体的六名不同患者建立的初级异种移植模型的试验 CRC。所有里程碑均已实现为追求临床的临床前概念证明 MTX-211的开发路径专门针对KRAS突变CRC种群。在第二阶段，我们建议在扩大的功效试验中测试更广泛的KRAS突变CRC模型，以便结合分子分析，以识别与治疗结果相关的预后标记。同时，我们建议进行早期的安全研究，以进一步脱发MTX-211并加强向未来的毒理学研究前进的案例。