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Development of a Dual and Selective Small Molecule Inhibitor of EGFR and PI3 Kinase to Treat BRAF Mutant Colorectal Cancer

开发 EGFR 和 PI3 激酶双重选择性小分子抑制剂来治疗 BRAF 突变结直肠癌

基本信息

批准号：
9896781
负责人：
Judith S Leopold
金额：
$ 45.49万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-17 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896781
关键词：
1-Phosphatidylinositol 3-Kinase Adopted BRAF gene Binding Biological Cancer Model Cecum Cells Clinical Clinical Treatment Clinical Trials Colorectal Colorectal Cancer Data Development Diagnosis Disease Dose Drug Kinetics Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exhibits Family member Future Gene Expression Profiling Goals Growth Human Implant In Vitro KRAS2 gene Lead Longevity MEKs Malignant Neoplasms Mediating Mitogen-Activated Protein Kinases Modeling Molecular Molecular Profiling Molecular Target Mus Mutation Neoplasm Metastasis Oncogenic PTEN gene Pathway interactions Patients Pattern Pharmacodynamics Pharmacologic Substance Phosphatidylinositide 3-Kinase Inhibitor Phosphotransferases Preclinical Testing Prognostic Marker Refractory Regimen Reporting Schedule Signal Transduction Signaling Molecule Specimen Survival Rate Testing Therapeutic Index Toxic effect Tumor Suppressor Proteins Valine Xenograft Model biomarker development cancer cell candidate marker clinical development colon cancer patients colorectal cancer treatment comparative comparative efficacy design drug candidate effective therapy efficacy study exome sequencing implantation improved improved outcome in vivo in vivo evaluation inhibitor/antagonist metastatic colorectal mutant novel outcome forecast patient subsets phosphoproteomics pre-clinical responders and non-responders response small molecule small molecule inhibitor success targeted agent therapy outcome treatment duration treatment strategy tumor tumor progression

项目摘要

Despite the emergence of an increased number of molecular targeted agents, the prognosis for patients with metastatic colorectal cancer (CRC) remains poor with 5 year survival rates of <10%. Agents targeting epidermal growth factor receptor (EGFR) have met with limited success in the clinical treatment of CRC and are limited to treatment of those patients whose tumors do not harbor mutations in KRAS or BRAF. Approximately 10% of colorectal malignancies are known to possess a BRAF valine 600 (BRAFV⁶⁰⁰) mutation, conferring an extremely poor prognosis. Reactivation of the MAP kinase pathway by EGFR and the co-occurrence of PIK3A mutations or loss of expression of the tumor suppressor PTEN serve to render BRAFmt tumors refractory to MEK or BRAF inhibitor monotherapies. Our central hypothesis is that a dual small molecule inhibitor that potently and selectively targets only EGFR and PI3KA in combination with an inhibitor of MAP kinase signaling represents a viable strategy for the treatment of BRAF mutant colorectal cancers. To test this hypothesis, we have designed small molecules that exhibit potent and selective dual inhibition of EGFR and PIK3A family members. To the best of our knowledge, the lead compound MTX-211 represents a first in class selective inhibitor of these two critical oncogenic kinases. We have generated crystallographic evidence confirming that MTX-211 binds to these two kinases in the manner predicted from its computational design, adopting a flipped binding mode to selectively and potently inhibit both EGFR and PI3K. Preliminary data have shown a striking increase in lifespan of mice implanted with patient-derived BRAFmt CRC when treated with the combination of MTX-211 and the MEK inhibitor trametinib. We now propose to carry out more extensive preclinical testing of MTX-211 in patient derived xenograft models established from patients diagnosed with BRAFmt CRC to bolster the case for this clinical development path. Molecular profiling will be carried out to elucidate markers that correlate with inherent sensitivity as well as the adaptive signaling changes that lead to progression. Additionally, we propose to maximize durability of response by carrying out comparative efficacy studies of MTX-211 combined with clinically approved MEK versus RAF inhibitors to inform the design of future clinical trials of this promising drug candidate for treatment of this recalcitrant disease.

尽管出现了越来越多的分子靶向药物，但患者的预后转移性结直肠癌（CRC）仍然很差，5 年生存率<10%。表皮靶向剂生长因子受体（EGFR）在结直肠癌的临床治疗中取得的成功有限，并且仅限于治疗那些肿瘤不带有 KRAS 或 BRAF 突变的患者。大约 10% 已知结直肠恶性肿瘤具有 BRAF 缬氨酸 600 (BRAFV⁶⁰⁰) 突变，赋予极其预后不良。 EGFR 对 MAP 激酶通路的重新激活与 PIK3A 突变的共存或肿瘤抑制因子 PTEN 表达缺失导致 BRAFmt 肿瘤对 MEK 或 BRAF 产生耐药性抑制剂单一疗法。我们的中心假设是，一种双重小分子抑制剂能够有效且仅选择性靶向 EGFR 和 PI3KA 与 MAP 激酶信号传导抑制剂相结合代表了治疗 BRAF 突变结直肠癌的可行策略。为了检验这个假设，我们设计了 small molecules that exhibit potent and selective dual inhibition of EGFR and PIK3A family members.至据我们所知，先导化合物 MTX-211 代表了这两种药物的一流选择性抑制剂关键的致癌激酶。我们已经生成了晶体学证据，证实 MTX-211 结合这两种激酶按照其计算设计预测的方式，采用翻转结合模式选择性且有效地抑制 EGFR 和 PI3K。初步数据显示寿命显着延长使用 MTX-211 和 MEK 联合治疗时，植入患者来源的 BRAFmt CRC 的小鼠的比例抑制剂曲美替尼。我们现在建议在患者衍生的 MTX-211 中进行更广泛的临床前测试从诊断为 BRAFmt CRC 的患者建立异种移植模型，以支持该临床案例发展路径。将进行分子分析以阐明与固有特征相关的标记物敏感性以及导致进展的适应性信号变化。此外，我们建议通过开展 MTX-211 与临床试验相结合的比较疗效研究，最大限度地提高反应的持久性批准 MEK 与 RAF 抑制剂的比较，为这种有前途的候选药物的未来临床试验设计提供信息用于治疗这种顽固性疾病。