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

• 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
• 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

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 机械疗法旨在设计，发现和开发选择性抑制肿瘤的抗癌药物。 多种致癌途径。它的主要药物MTX-211是与利奥波德合作发现的。 密歇根大学的实验室。该项目的总体目标是方便地推进MTX- 211开发用于治疗KRAS突变型结直肠癌（CRC）。每年> 13万 新的患者被诊断患有结肠直肠癌。在诊断时，大约20%的人 存在转移性疾病的患者。目前，没有批准的转移性肿瘤的治疗方法。 具有KRAS激活突变的CRC患者。MTX-211是一流的高选择性双重抑制剂 PI 3 K和EGFR激酶的合成，旨在使用两个正交信号来攻击KRAS致癌信号传导 机制等因此，它在单个分子中体现了组合方法。第一阶段的目标集中在 优化MTX-211的合成工艺，扩大生产规模， 从诊断为KRAS突变的六名不同患者建立的原发性异种移植模型的试验 《儿童权利公约》。实现了所有里程碑，为临床研究提供了临床前概念验证。 MTX-211特异性靶向KRAS突变型CRC人群的开发路径。在第二阶段， 我们建议在一项扩大的疗效试验中测试更广泛的KRAS突变型CRC模型， 结合分子谱分析以鉴定与治疗结果相关的预后标志物。 与此同时，我们建议开展早期安全性研究，以进一步降低MTX-211的风险并加强 推进未来IND毒理学研究的案例。