Targeting ERK5 for Colorectal Cancer Therapy

靶向 ERK5 的结直肠癌治疗

基本信息

批准号：
10357462
负责人：
GARTH POWIS
金额：
$ 16.95万
依托单位：
PHUSIS THERAPEUTICS, INC.
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357462
关键词：
BRAF gene Cancer Center Cell Differentiation process Cell Proliferation Cells Clinic Clinical Clinical Research Clinical Trials Colorectal Cancer Cytokine Receptors Data Development Diagnosis Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Family member Feedback Genetic Growth Factor Human In Vitro Investigational Therapies KRAS oncogenesis KRAS2 gene Lead MAP Kinase Gene MAP2K1 gene MAPK Signaling Pathway Pathway MAPK phosphatase MAPK3 gene MAPK7 gene MEKs Malignant Neoplasms Malignant neoplasm of lung Mediating Mitogen-Activated Protein Kinase Inhibitor Molecular Mus Mutation Neoplasm Metastasis Organoids Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Play Publications Ras/Raf Receptor Protein-Tyrosine Kinases Research Project Grants Resistance Role Sampling Signal Pathway Signal Transduction Specificity Testing Therapeutic Tumor stage Up-Regulation adenoma base cancer cell colon cancer cell line colon cancer patients colorectal cancer metastasis colorectal cancer treatment effective therapy gain of function mutation in vivo inhibitor/antagonist intestinal epithelium intestinal homeostasis melanoma mortality mutant novel patient derived xenograft model patient response pre-clinical preservation prevent resistance mechanism response stem cells targeted agent targeted treatment therapeutic target therapy resistant treatment response tumor tumor growth 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 or acquired resistance to targeted therapy is a major obstacle, particularly in CRC as compared with other cancers such as melanoma and lung cancer. 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 the studies reactivation of MAPK signaling was identified as a cause of resistance and low patient response rates. The mechanism of the reactivation of 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 mechanism causing ERK5 upregulation 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, invasion 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）结合使用防止其反馈激活的抑制剂对CRC的全身治疗有望。但是，主要或获得靶向治疗的抗药性是一个主要障碍，尤其是在CRC中黑色素瘤和肺癌等癌症。 EGFR/RAF或RAF/MEK抑制剂的组合已经在实验室和诊所进行了测试，最近对三重抑制剂鸡尾酒（EGFR/RAF/MEK）进行了临床评估在BRAFV600E突变体CRC中。但是，在所有研究中，MAPK信号的重新激活都被确定为原因抵抗力和患者反应率低。 MAPK信号重新激活的机制很差理解齿。我们在遗传缺失后发现了肠上皮细胞中的一种新型抗性机制体内小鼠中的ERK1/2，以及用MEK抑制剂在体外对人CRC细胞的治疗。这分子机制涉及非典型MAPK家族成员ERK5的激活，该成员提供了旁路通往规范MAPK信号通路的信号通路。研究是基于“ ERK5的治疗靶向，尤其是当RAS或BRAF是癌症驱动器时，与其他靶向剂和/或化学治疗剂的结合将增强CRC增殖的抑制作用和转移。 ERK5与EGFR，RAF和/或MEK抑制剂的药理靶向将在致癌性KRAS或BRAF突变的CRC患者中特别有效，因为这种方法可防止通过平行途径获得的抗性”。我们将进行的研究是：研究分子引起CRC细胞中ERK5上调的机制；评估患者来源的CRC中的ERK5信号传导带有KRAS突变的样品；以及对MEK抑制剂耐药者CRC患者的治疗投资带有ERK5靶向剂的Xenographictics。这是一个探索性发展研究项目，以获取临床前数据验证了潜在的新临床目标ERK5，负责肿瘤进展，侵袭和转移 CRC。获得的信息将为ERK5抑制剂组合的临床试验提供基础与CRC患者一起使用EGFR/ RAF/ MEK抑制剂鸡尾酒。