Targeting ERK5 for Colorectal Cancer Therapy

靶向 ERK5 的结直肠癌治疗

• 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
• 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

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.

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，以防止其反馈激活持有的CRC的全身治疗的希望。但小学 或获得性耐药的靶向治疗是一个主要障碍，特别是在CRC相比，其他 癌症如黑色素瘤和肺癌。EGFR/RAF或RAF/MEK抑制剂的组合已经被广泛应用。 在实验室和临床测试，最近三重抑制剂鸡尾酒（EGFR/RAF/MEK）已进行临床评估 在BRAFV 600 E突变CRC中。然而，在所有的研究中，MAPK信号的重新激活被确定为一个原因， 抵抗和低病人反应率。MAPK信号通路的再激活机制尚不清楚， 明白我们发现，在基因缺失后，肠上皮细胞中存在一种新的耐药机制 ERK 1/2在小鼠体内以及在体外对用MEK抑制剂处理人CRC细胞的响应。这 分子机制涉及非典型MAPK家族成员ERK 5的激活，其提供旁路 MAPK信号通路的信号通路。因此，研究所依据的假设 基于“ERK 5的治疗靶向，特别是当RAS或BRAF是癌症驱动因素时， 与其它靶向剂和/或化学治疗剂的组合将增强CRC增殖的抑制 和转移。ERK 5与EGFR、RAF和/或MEK抑制剂组合的药理学靶向将 在具有致癌KRAS或BRAF突变的CRC患者中特别有效，因为这种方法可以防止 通过平行途径获得抗性”。我们将进行的研究是： 导致CRC细胞中ERK 5上调的机制;在患者来源的CRC中评价ERK 5信号传导 具有KRAS突变的样本;以及一项针对MEK受体耐药CRC患者的治疗研究， 用ERK 5靶向剂进行异种移植。这是一个探索性的发展研究项目，以获得临床前 数据验证了一个潜在的新的临床靶点，ERK 5，负责肿瘤的进展，侵袭和转移 CRC。所获得的信息将为ERK 5抑制剂， EGFR/RAF/ MEK抑制剂混合物治疗CRC患者。