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.

抽象的 美国约有 140,000 名患者被诊断出结直肠癌 (CRC)，其中 50,000 名患者死亡 每年。这些患者中几乎一半有 RAS 或 BRAF 突变，但目前尚无相关证据。 有效的治疗。激活的 MAPK 信号在 CRC 的发病机制中发挥着重要作用。药理作用 突变体 BRAFV600E、MEK1/2 和最近的 ERK1/2 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) 组合 阻止其反馈激活的抑制剂有望用于结直肠癌的系统治疗。然而，初级 与其他疾病相比，对靶向治疗的耐药性或获得性耐药是一个主要障碍，特别是在结直肠癌中 癌症，如黑色素瘤和肺癌。 EGFR/RAF 或 RAF/MEK 抑制剂的组合已被 在实验室和临床上进行了测试，最近三重抑制剂混合物（EGFR/RAF/MEK）已经过临床评估 在 BRAFV600E 突变 CRC 中。然而，在所有研究中，MAPK 信号传导的重新激活被确定为原因 耐药性和患者反应率低。 MAPK信号重新激活的机制尚不明确 明白了。我们在肠上皮细胞中发现了一种新的耐药机制，即基因删除 小鼠体内的 ERK1/2，以及体外对用 MEK 抑制剂处理人类 CRC 细胞的反应。这 分子机制涉及非典型 MAPK 家族成员 ERK5 的激活，它提供了一个旁路 信号通路至经典 MAPK 信号通路。因此，研究所依据的假设 其基础是“ERK5 的治疗靶向，特别是当 RAS 或 BRAF 是癌症驱动因素时， 与其他靶向药物和/或化疗药物组合将增强对 CRC 增殖的抑制 和转移。 ERK5 与 EGFR、RAF 和/或 MEK 抑制剂组合的药理学靶向将 对于具有致癌 KRAS 或 BRAF 突变的 CRC 患者特别有效，因为这种方法可以预防 通过平行途径获得耐药性”。我们将进行的研究是：调查分子 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 具有 KRAS 突变的样本；以及对 MEK 抑制剂耐药的 CRC 患者的治疗研究 使用 ERK5 靶向药物进行异种移植。这是一个探索性开发研究项目，旨在获得临床前 数据验证了潜在的新临床靶点 ERK5，该靶点负责肿瘤进展、侵袭和转移 CRC 的。获得的信息将为 ERK5 抑制剂组合的临床试验提供基础， 在 CRC 患者中使用 EGFR/RAF/MEK 抑制剂混合物。