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

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

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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. 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。 MTX-211是一种新型激酶抑制剂，表现出早期的希望针对固体癌症对当前治疗方案难治性的治疗潜力。这个sttr的目标应用是要证明将MTX-211开发为科学优点和治疗可行性治疗KRAS突变结肠癌。每年> 130,000名新患者被诊断出结肠直肠癌症。在诊断时，这些患者中约有20％出现转移性疾病。诊断为转移性结肠癌（MCRC）的患者预后非常差，生存率为5年比率小于15％。这些患者中的一小部分对使用EGFR响应第一线治疗单克隆抗体（西妥昔单抗或panitumumab）。但是，这些代理商赋予了50％的50％ MCRC患者的肿瘤患者在KRAS癌基因中具有突变。目前，没有对KRAS激活突变的MCRC患者的批准治疗。 MTX-211是一流的双重二元 PI3K和EGFR激酶的抑制剂，表现出对多个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攻击KRAS致癌信号传导机制，用作单分子中的组合方法。与以前报道的双重受体酪氨酸和脂质激酶抑制剂，MTX-211对于EGFR和PI3K家族成员具有很高的选择性。因此，它具有限制脱靶毒性和广泛的治疗窗口。这个长期目标建议是改善诊断为转移性结直肠癌的患者的临床结果与KRAS中的激活突变。在特定的目标1中，我们将在20克时扩展MTX-211的合成比例生成足够的特定目标材料。在特定目标2中，我们建议评估功效 MTX-211针对六个KRAS突变CRC PDX模型。所有六个模型的组织学已得到证实为了概括原始患者标本的标本，所有这些标本都由整个外显子组完全介绍测序。将遵循该试验试验中的总体响应率为30％的成功证明通过II期计划，对更广泛的CRC PDX面板进行了MTX-211的扩展小鼠试验。这以精确药物为中心的II期提案的预期结果将是一个明确定义的患者富集策略并确定预后标记，以响应双重跟踪治疗结果用MTX-211抑制EGFR/PI3K途径。联合第I和II期应用程序将提供关键证明完成调查新药（IND）软件包所必需的数据。