Targeting ERK5 for Colorectal Cancer Therapy

靶向 ERK5 的结直肠癌治疗

基本信息

批准号：
10021322
负责人：
GARTH POWIS
金额：
$ 27.35万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-13 至 2021-01-13
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10021322
关键词：
ACVR1 gene BRAF gene Binding Cancer Center Cell Nucleus Cell Proliferation Cessation of life Clinic Clinical Clinical Research Clinical Trials Colorectal Cancer Data Development Diagnosis Embryo Embryonic Development Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Exhibits Family member Feedback Genetic Human Hypoxia In Vitro Investigational Therapies KRAS2 gene Knockout Mice Lead MAP Kinase Gene MAP2K1 gene MAPK Signaling Pathway Pathway MAPK3 gene MAPK7 gene MEKs Malignant Neoplasms Malignant neoplasm of lung Mediating Mitogen-Activated Protein Kinase Kinases Molecular Mus Mutation Neoplasm Metastasis Nuclear Translocation Oncogenic Organoids Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Play Proto-Oncogenes Ras/Raf Receptor Protein-Tyrosine Kinases Reporting Research Project Grants Residual state Resistance Response Elements Role Sampling Signal Pathway Signal Transduction Testing Transcription Coactivator Tumor Angiogenesis Tumor Suppressor Proteins Tumor stage Up-Regulation Vascular Endothelial Growth Factors Xenograft procedure adenoma angiogenesis base beta catenin blood vessel development cancer cell cancer type cell growth colon cancer cell line colon cancer patients colon carcinogenesis colorectal cancer metastasis colorectal cancer treatment effective therapy hypoxia inducible factor 1 in vivo inhibitor/antagonist intestinal epithelium melanoma mortality mutant neoplastic cell novel patient response pre-clinical prevent promoter resistance mechanism response targeted agent targeted treatment therapeutic target therapy resistant treatment response tumor tumor growth tumor hypoxia tumor progression

ACVR1 gene BRAF gene Binding Cancer Center Cell Nucleus Cell Proliferation Cessation of life Clinic Clinical Clinical Research Clinical Trials Colorectal Cancer Data Development Diagnosis Embryo Embryonic Development Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Exhibits Family member Feedback Genetic Human Hypoxia In Vitro Investigational Therapies KRAS2 gene Knockout Mice Lead MAP Kinase Gene MAP2K1 gene MAPK Signaling Pathway Pathway MAPK3 gene MAPK7 gene MEKs Malignant Neoplasms Malignant neoplasm of lung Mediating Mitogen-Activated Protein Kinase Kinases Molecular Mus Mutation Neoplasm Metastasis Nuclear Translocation Oncogenic Organoids Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Play Proto-Oncogenes Ras/Raf Receptor Protein-Tyrosine Kinases Reporting Research Project Grants Residual state Resistance Response Elements Role Sampling Signal Pathway Signal Transduction Testing Transcription Coactivator Tumor Angiogenesis Tumor Suppressor Proteins Tumor stage Up-Regulation Vascular Endothelial Growth Factors Xenograft procedure adenoma angiogenesis base beta catenin blood vessel development cancer cell cancer type cell growth colon cancer cell line colon cancer patients colon carcinogenesis colorectal cancer metastasis colorectal cancer treatment effective therapy hypoxia inducible factor 1 in vivo inhibitor/antagonist intestinal epithelium melanoma mortality mutant neoplastic cell novel patient response pre-clinical prevent promoter resistance mechanism response targeted agent targeted treatment therapeutic target therapy resistant treatment response tumor tumor growth tumor hypoxia tumor progression

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项目摘要

ABSTRACT Colorectal cancer (CRC) is diagnosed in about 140,000 patients in the US, with a mortality of 50,000 patients per year. Almost half of these patients have either a RAS or BRAF mutation for which there is currently no effective therapy. Activated MAPK signaling plays a major role in the pathogenesis of CRC. Pharmacological inhibitors of mutant BRAFV600E, MEK1/2, and more recently ERK1/2 have been developed for targeted therapy. Vertical targeting the MAPK pathway, particularly in combination with epidermal growth factor receptor (EGFR) inhibitors to prevent its feedback activation, holds promise for the systemic treatment of CRC. However, primary resistance to targeted therapy is a major obstacle in CRC, as compared with other cancers such as melanoma and lung cancer which exhibit acquired resistance to therapy. Combinations of EGFR/RAF or RAF/MEK inhibitors have been tested in the lab and clinic, and recently a triple inhibitor cocktail (EGFR/RAF/MEK) has been clinically evaluated in BRAFV600E mutant CRC. However, in all studies residual MAPK signaling was identified as a cause of resistance with low patient response rates. The mechanism of the residual MAPK signaling is poorly understood. We have found a novel resistance mechanism in intestinal epithelial cells upon genetic deletion of ERK1/2 in mice in vivo, as well as in response to treatment of human CRC cells with MEK inhibitors in vitro. This molecular mechanism involves activation of an atypical MAPK family member, ERK5, which provides a by-pass signaling pathway to the canonical MAPK signaling pathway. Thus, the hypothesis upon which the studies are based is that “therapeutic targeting of ERK5, particularly when either RAS or BRAF is the cancer driver, in combination with other targeted agents and/or chemotherapeutics will enhance inhibition of CRC proliferation and metastasis. Pharmacological targeting of ERK5 in combination with EGFR, RAF and/or MEK inhibitors will be particularly effective in CRC patients with oncogenic KRAS or BRAF mutations, as this approach prevents acquired resistance via parallel pathways”. The studies we will conduct are to: investigate the molecular mechanisms causing ERK5 upregulation in CRC and the role of ERK5 as a transcriptional activator of angiogenesis in CRC cells; evaluate of ERK5 signaling in patient-derived CRC samples with KRAS mutations; and an investigation of treatment of MEK inhibitor-resistant CRC patient derived xenografts with ERK5 targeted agents. This an exploratory developmental research project to obtain preclinical data validating a potential new clinical target, ERK5, responsible for tumor progression, angiogenesis and metastasis of CRC. The information obtained will provide the basis for a clinical trial of the combination of an ERK5 inhibitor, with an EGFR/RAF/ MEK inhibitor cocktail in CRC patients.

抽象的在美国约有14万名患者中，结直肠癌（CRC）被诊断出死亡率为50,000例每年。这些患者中几乎有一半的RAS或BRAF突变目前没有有效的疗法。活化的MAPK信号在CRC的发病机理中起主要作用。药理已开发了用于靶向治疗的突变体BRAFV600E，MEK1/2和ERK1/2的抑制剂。垂直靶向MAPK途径，特别是与表皮生长因子受体（EGFR）结合使用抑制剂可以防止其反馈激活，对CRC进行全身治疗有望。但是，主要与其他癌症（例如黑色素瘤）相比暴露于对治疗的抵抗力的肺癌。 EGFR/RAF或RAF/MEK的组合抑制剂已在实验室和诊所进行了测试，最近三重抑制剂鸡尾酒（EGFR/RAF/MEK）具有在BRAFV600E突变体CRC中进行了临床评估。但是，在所有研究中，残留的MAPK信号是被确定为患者反应率较低的阻力原因。残留MAPK的机制信号传递知之甚少。我们在肠上皮细胞中发现了一种新颖的抗性机制体内小鼠ERK1/2的遗传缺失，以及对用MEK治疗人CRC细胞的遗传缺失体外抑制剂。这种分子机制涉及非典型MAPK家族成员ERK5的激活它为典型的MAPK信号通路提供了旁路信号通路。那是假设研究基于的是“ ERK5的治疗性靶向，尤其是在RAS或BRAF时是癌症驱动器，与其他靶向剂和/或化学治疗剂结合使用会增强抑制作用 CRC增殖和转移。 ERK5与EGFR，RAF和/或 MEK抑制剂将在致癌性KRAS或BRAF突变的CRC患者中特别有效，因为方法可以防止通过平行途径获得获得的抵抗”。我们将进行的研究是：调查导致CRC中ERK5上调的分子机制和ERK5作为转录激活剂的作用 CRC细胞中血管生成；评估具有KRAS突变的患者衍生的CRC样品中的ERK5信号传导；以及对MEK抑制剂耐CRC患者的治疗投资，具有ERK5为目标代理商。这是一个探索性发展研究项目，旨在获取临床前数据，以验证潜在的新临床靶标，ERK5，负责CRC的肿瘤进展，血管生成和转移。信息获得的将为ERK5抑制剂与EGFR/RAF/的临床试验提供基础 CRC患者的MEK抑制剂鸡尾酒。