Novel small molecule inhibitors of MEK5_ERK5 for the treatment of breast cancer

用于治疗乳腺癌的新型 MEK5_ERK5 小分子抑制剂

• 批准号: 8626554
• 负责人: JANE E CAVANAUGH
• 金额: $ 39.42万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626554
• 关键词: Abnormal Cell; Address; Animal Model; Biochemical; Biological Assay; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast Carcinoma; Cancer Biology; Cancer Cell Growth; Cancer Model; Cancer Patient; Cancer cell line; Cell Line; Cell Proliferation; Cells; Clinical Trials; Data; Development; Disease Progression; Disease-Free Survival; Family; Feedback; Goals; Growth; Hela Cells; Hormonal; Human; In Vitro; MAP2K1 gene; MAPK3 gene; MAPK7 gene; MCF7 cell; MDA MB 231; MEKs; Malignant Neoplasms; Mammary Neoplasms; Measures; Mediating; Mesothelioma; Methods; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Neoplasm Metastasis; Pathology; Pathway interactions; Patients; Phase; Phosphatidylinositide 3-Kinase Inhibitor; Phosphatidylinositols; Phosphotransferases; Process; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Testing; Therapeutic Intervention; Tissues; Training; base; cancer cell; cancer therapy; cancer type; cell growth; cell motility; graduate student; high school; improved; in vivo; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; member; migration; mortality; mouse model; new therapeutic target; novel; prevent; protein expression; public health relevance; research study; small molecule; tumor; tumor progression; tumorigenesis; undergraduate student

Project Summary/Abstract Dyregulation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositide-3-kinase (PI3K) pathways has been implicated in breast cancer pathology. Activation of the MEK1/2-ERK1/2 MAPK and the PI3K/Akt cascades in breast cancer increases cell proliferation and sustains tumor survival. Further, interaction between these pathways has been implicated in chemoresistance, suggesting that dual inhibition of these pathways may be necessary to prevent breast cancer growth and metastasis. The newest member of the MAPK family of kinases, the MEK5-ERK5 pathway, has been shown to enhance cancer cell growth and increase patient mortality. More specifically, increased ERK5 activation has been associated with decreased disease-free survival in breast cancer patients and signaling crosstalk with the PI3K pathway has been demonstrated in other cancer models. Therapies that target the MEK1/2-ERK1/2 pathways are used clinically and inhibitors of the PI3K/Akt pathway are in Phase I and II clinical trials for breast cancer. While there are currently 3 small molecule inhibitors of MEK5-ERK5 signaling available only one has been tested in breast cancer models. Moreover, in some breast cancer cells, these inhibitors are not specific for the MEK5-ERK5 pathway and, in some cases, even increase ERK5 activation. Therefore, there is a need for novel small molecule inhibitors that are specific for the MEK5-ERK5 pathway that may be clinically useful alone or in combination with other kinase inhibitors. The goal of this proposal is to test small molecule inhibitors of MEK5 that we developed in in vitro and in vivo breast cancer models and to use these novel inhibitors and biochemical methods to examine crosstalk between the MEK5-ERK5 and PI3K/Akt pathways in breast carcinoma. Therefore, the aims of this proposal seek to test the hypothesis that novel small molecule inhibitors of MEK5-ERK5 decrease tumorigenesis, migration, and metastasis and enhance the anti-proliferative effects of PI3K/Akt inhibitors in breast cancer. Breast cancer cell lines with distinct hormonal profiles will be employed and a breast cancer-xenograph mouse model will be used to examine the effect of the MEK5 inhibitors on breast tumor progression and metastasis. The experiments proposed in this application will provide a greater mechanistic understanding of the MEK5-ERK5 pathway, potentially leading to the development of novel, targeted therapeutics for breast cancer patients. Further, a more comprehensive understanding of the MEK5-ERK5 pathway may have widespread implications for various cancer types, adding to the significance of the proposal. These aims will also provide a stimulating training opportunity for undergraduate and graduate students to actively participate in the research and discovery processes to improve our understanding of signal transduction in cancer biology.

项目摘要/摘要 有丝分裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3-激酶（PI3K）的染色调节 途径与乳腺癌病理有关。 MEK1/2-ERK1/2 MAPK的激活和 乳腺癌中的PI3K/AKT级联会增加细胞增殖并维持肿瘤的存活。此外，相互作用 这些途径之间与化学抗性有关，表明对这些途径的双重抑制 预防乳腺癌生长和转移可能是必要的途径。最新成员 MAPK激酶家族（MEK5-ERK5途径）已被证明可以增强癌细胞的生长和 增加患者死亡率。更具体地说，ERK5激活增加与减少有关 乳腺癌患者的无病生存和与PI3K途径的信号传导串扰 在其他癌症模型中证明。使用针对MEK1/2-ERK1/2途径的疗法 PI3K/AKT途径的临床和抑制剂正在乳腺癌的I和II期临床试验中。尽管 目前有3个MEK5-ERK5信号的小分子抑制剂可用 在乳腺癌模型中进行了测试。此外，在某些乳腺癌细胞中，这些抑制剂并非特定于 MEK5-ERK5途径，在某些情况下，甚至会增加ERK5激活。因此，有必要 对于可能是临床上可能是MEK5-ERK5途径的新型小分子抑制剂 单独使用或与其他激酶抑制剂结合使用。该提议的目的是测试小 我们在体外和体内乳腺癌模型中开发的MEK5的分子抑制剂并使用 这些新型抑制剂和生化方法检查MEK5-ERK5和 乳腺癌中的PI3K/AKT途径。因此，该提议的目的旨在检验以下假设 MEK5-ERK5的新型小分子抑制剂减少了肿瘤发生，迁移和转移和转移 增强PI3K/AKT抑制剂对乳腺癌的抗增殖作用。乳腺癌细胞系 将采用独特的激素特征，并将使用乳腺癌 - Xenography小鼠模型 检查MEK5抑制剂对乳腺肿瘤进展和转移的影响。实验 在本应用程序中提出的将提供对MEK5-ERK5途径的更多机械理解， 有可能导致开发针对乳腺癌患者的新型，有针对性的治疗剂。更远， 对MEK5-ERK5途径的更全面的了解可能对 各种癌症类型，增加了提案的重要性。这些目标还将提供刺激性 培训本科生和研究生积极参与研究的机会 发现过程以提高我们对癌症生物学信号转导的理解。