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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

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.

摘要在美国约有140，000名患者被诊断为结直肠癌（CRC），其中50，000名患者死亡每一年。这些患者中几乎有一半患有RAS或BRAF突变，目前还没有有效的治疗。活化的MAPK信号在CRC的发病机制中起主要作用。药理突变型BRAFV 600 E、MEK 1/2和最近ERK 1/2的抑制剂已被开发用于靶向治疗。垂直靶向MAPK通路，特别是与表皮生长因子受体（EGFR）联合使用抑制剂，以防止其反馈激活，为CRC的全身治疗带来了希望。但小学与其他癌症如黑色素瘤相比，对靶向治疗的抗性是CRC的主要障碍和对治疗表现出获得性抗性的肺癌。EGFR/RAF或RAF/MEK的组合抑制剂已经在实验室和临床上进行了测试，最近一种三重抑制剂鸡尾酒（EGFR/RAF/MEK）已经在在BRAFV 600 E突变型CRC中进行了临床评价。然而，在所有研究中，被确定为耐药的原因，患者应答率低。残余MAPK的作用机制对信号的理解很少。我们已经在肠上皮细胞中发现了一种新的耐药机制，小鼠体内ERK 1/2的基因缺失，以及对MEK处理人CRC细胞的反应体外抑制剂。这种分子机制涉及非典型MAPK家族成员ERK 5的激活，其为经典MAPK信号通路提供旁路信号通路。因此，假设研究所基于的是“ERK 5的治疗靶向，特别是当RAS或BRAF 是癌症驱动因素，与其他靶向药物和/或化疗药物组合将增强抑制作用 CRC的增殖和转移。ERK 5与EGFR、RAF和/或EGFR的组合的药理学靶向 MEK抑制剂在具有致癌KRAS或BRAF突变的CRC患者中将特别有效，因为这是一种有效的抑制剂。这种方法通过平行途径防止获得性耐药性”。我们将进行的研究是：调查 ERK 5在结直肠癌中上调的分子机制及其作为转录激活因子的作用在具有KRAS突变的患者来源的CRC样品中评估ERK 5信号传导; 以及用ERK 5靶向治疗MEK受体抗性CRC患者来源的异种移植物的研究剂.这是一个探索性的开发研究项目，以获得临床前数据，验证潜在的新的临床靶点ERK 5负责肿瘤进展、血管生成和CRC转移。的信息获得的结果将为ERK 5抑制剂与EGFR/RAF/EGFR抑制剂的组合的临床试验提供基础。 CRC患者中的MEK抑制剂鸡尾酒。