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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：
9255740
负责人：
Judith S Leopold
金额：
$ 27.5万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9255740
关键词：
1-Phosphatidylinositol 3-Kinase Advanced Development Antineoplastic Agents Assimilations Cancer Etiology Cancer Prognosis Capital Cessation of life Cetuximab Chemistry Clinical Clinical Trials Collaborations Colorectal Colorectal Cancer Colorectal Neoplasms Combined Modality Therapy Custom Data Development Diagnosis Disease Dose Drug Interactions Economics Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Evaluation Family member Funding Genomics Goals HCT116 Cells Heterogeneity Histology Impairment Individual Investments KRAS2 gene Laboratories Lead Lipids Malignant Neoplasms Measures Michigan Modeling Monoclonal Antibodies Mus Mutation Newly Diagnosed Oncogenes Oncogenic Outcome PTEN gene Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phosphotransferases Process Prognostic Marker Protein Isoforms Public Health Refractory Regimen Reporting Risk Route Signal Transduction Signaling Molecule Small Business Technology Transfer Research Solid Specimen Survival Rate Testing Therapeutic Time Toxic effect Toxicology Tyrosine United States Universities Validation Vertebral column Xenograft Model Xenograft procedure anticancer activity chemotherapy clinical development colon cancer patients commercial application design effective therapy exome sequencing fluoropyrimidine improved in vivo inhibitor/antagonist innovation irinotecan kinase inhibitor metastatic colorectal mutant mutational status neoplastic cell novel novel therapeutics outcome forecast oxaliplatin panitumumab patient population phase 2 study pilot trial pre-clinical precision medicine prototype receptor response scale up single molecule success targeted treatment therapeutic development therapy development therapy outcome tumor

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. MTX-211 is a novel kinase inhibitor showing early promise for its therapeutic potential against solid cancers refractory to current treatment options. The goal of this STTR application is to demonstrate the scientific merit and therapeutic feasibility of developing MTX-211 to treat KRAS mutant colorectal cancers. 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. Patients diagnosed with metastatic colorectal cancer (mCRC) have a very poor prognosis, with 5 year survival rates of less than 15%. A small percentage of these patients respond to first line treatment with EGFR monoclonal antibodies (cetuximab or panitumumab). However, these agents confer no benefit to the 50% of the mCRC patient population whose tumors harbor a mutation in the KRAS oncogene. Currently, there are no approved treatments for mCRC patients with activating mutations in KRAS. MTX-211 is a first-in-class dual inhibitor of PI3K and EGFR kinases with demonstrated in vivo anticancer activity against multiple KRAS mutant colorectal tumors. MTX-211 is innovative because it attacks KRAS oncogenic signaling using two orthogonal mechanisms, serving as a combination approach in a single molecule. Unlike previously reported dual receptor tyrosine and lipid kinase inhibitors, MTX-211 is highly selective for EGFR and PI3K family members. As such, it has limited off-target toxicity and a broad therapeutic window. The long-term goal of this proposal is to improve the clinical outcome of patients diagnosed with metastatic colorectal cancer with activating mutations in KRAS. In Specific Aim 1, we will scale up synthesis of MTX-211 at the 20 gram scale to generate sufficient materials for Specific Aim 2. In Specific Aim 2, we propose to evaluate the efficacy of MTX-211 against six KRAS mutant CRC PDX models. The histology of all six models has been confirmed to recapitulate that of the original patient specimen and all have been fully profiled by whole exome sequencing. Successful demonstration of an overall response rate of 30% in this pilot trial would be followed by a Phase II plan to conduct an expanded mouse trial of MTX-211 against a broader CRC PDX panel. The expected outcome of a precision medicine-focused Phase II proposal would be a clearly defined patient enrichment strategy and identified prognostic markers that track therapeutic outcome in response to dual inhibition of EGFR/PI3K pathways with MTX-211. Combined Phase I and II applications will provide pivotal data necessary to justify completing an investigative new drug (IND) package.

项目概要 Mekanistic Therapeutics 致力于设计、发现和开发选择性抑制癌症的抗癌药物多种致癌途径。其主要药剂 MTX-211 是与利奥波德合作发现的密歇根大学实验室。 MTX-211 是一种新型激酶抑制剂，显示出其早期应用前景针对当前治疗方案难以治愈的实体癌的治疗潜力。本 STTR 的目标申请的目的是证明开发 MTX-211 的科学价值和治疗可行性治疗 KRAS 突变结直肠癌。每年有超过 130,000 名新患者被诊断患有结直肠癌癌症。在诊断时，大约 20% 的患者出现转移性疾病。诊断为转移性结直肠癌 (mCRC) 的患者预后非常差，生存期为 5 年率低于15%。这些患者中的一小部分对 EGFR 一线治疗有反应单克隆抗体（西妥昔单抗或帕尼单抗）。然而，这些药物并没有给这 50% 的人带来任何好处。肿瘤中含有 KRAS 癌基因突变的 mCRC 患者群体。目前，没有批准治疗具有 KRAS 激活突变的 mCRC 患者。 MTX-211 是一款一流的双 PI3K 和 EGFR 激酶抑制剂，具有针对多种 KRAS 突变体的体内抗癌活性结直肠肿瘤。 MTX-211 具有创新性，因为它使用两个正交的信号来攻击 KRAS 致癌信号机制，作为单个分子的组合方法。与之前报道的双 MTX-211 是受体酪氨酸和脂质激酶抑制剂，对 EGFR 和 PI3K 家族成员具有高度选择性。因此，它具有有限的脱靶毒性和广泛的治疗窗口。本次活动的长远目标该提案旨在改善诊断为转移性结直肠癌的患者的临床结果激活 KRAS 突变。在具体目标 1 中，我们将按 20 克规模放大 MTX-211 的合成规模为特定目标 2 生成足够的材料。在特定目标 2 中，我们建议评估功效 MTX-211 对抗六种 KRAS 突变 CRC PDX 模型。所有六种模型的组织学均已得到证实概括原始患者标本的情况，并且所有标本均已通过整个外显子组进行了全面分析测序。在此试点试验中将成功展示 30% 的总体缓解率 II 期计划针对更广泛的 CRC PDX 小组进行 MTX-211 的扩大小鼠试验。这以精准医学为重点的第二阶段提案的预期结果将是明确定义的患者富集策略和确定的预后标记物，可跟踪双重治疗的治疗结果 MTX-211 抑制 EGFR/PI3K 通路。第一阶段和第二阶段的联合应用将提供关键的证明完成研究性新药 (IND) 包的必要数据。