RET as a novel therapeutic target for breast cancer

RET作为乳腺癌的新治疗靶点

基本信息

批准号：
9031089
负责人：
RONALD J WEIGEL
金额：
$ 34.54万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-06 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9031089
关键词：
1-Phosphatidylinositol 3-Kinase Apoptosis Breast Cancer Cell Breast Cancer Patient Breast Cancer therapy CASP3 gene Cleaved cell Clinical Clinical Trials Clinical effectiveness Combined Modality Therapy Data Development ESR1 gene Effectiveness Epidermal Growth Factor Receptor Epigenetic Process Estrogen Antagonists Estrogen Receptor alpha FRAP1 gene Gene Expression Regulation Gene Targeting Genes Health Hormones In Situ Nick-End Labeling Institutional Review Boards Ligands MEKs Malignant Neoplasms Measures Mediating Molecular Molecular Target Outcome Pathway interactions Patients Placebos Post-Translational Protein Processing Proteins Proto-Oncogenes Randomized Randomized Clinical Trials Receptor Protein-Tyrosine Kinases Regulation Resistance Role S Phase Signal Pathway TFAP2A gene TFAP2C gene Testing Therapeutic Translating Tumor Markers Tumor Tissue Tyrosine Kinase Inhibitor base cell growth chromatin modification clinically relevant hormone resistance hormone therapy inhibitor/antagonist knock-down malignant breast neoplasm molecular marker new therapeutic target novel overexpression pre-clinical prospective response therapeutic target transcription factor treatment response tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The TFAP2C/AP-2α transcription factor regulates the expression of a number of key genes that control oncogenesis and progression in breast cancer. Amplification of the TFAP2C gene locus is common in cancer and overexpression of TFAP2C is associated with a worse clinical outcome. TFAP2C regulates the expression of estrogen receptor-alpha (ERa)-associated genes including the RET proto-oncogene encoding a receptor tyrosine kinase (RTK), which is expressed more commonly in ERa-positive luminal breast cancers. Our recent findings identified RET as a novel therapeutic target in breast cancer. Ligand-activated RET regulates cell growth through the activation of multiple signaling pathways including the MAP kinase/ERK and PI3 kinase/Akt pathways. Knockdown of RET expression or treatment with tyrosine kinase inhibitors (TKI) with anti-RET activity such as sunitinib or vandetanib induces apoptosis of breast cancer cells. Whereas anti-estrogens block proliferation (measured by S-phase or Ki-67), anti-RET therapy induces apoptosis (measured by cleaved caspase 3 (CC3) or TUNEL), with combination therapy resulting in greater response than either alone. Furthermore, blocking RET activity can increase sensitivity to anti-estrogens and has the potential to induce hormone response in hormone unresponsive breast cancers. The response of primary breast cancers to TKI is dependent upon RET expression, indicating that RET may be used as a marker to predict therapeutic response to TKI therapy. The expression of EGFR is also regulated by TFAP2C and recent evidence suggests that in some breast cancers TKIs with activity against both RET and EGFR, such as vandetanib, may offer greater clinical effectiveness. We hypothesize that RET is a novel therapeutic target for breast cancer therapy; we further hypothesize that EGFR may cooperate with RET and co-targeting these RTKs may be effective in breast cancer. We propose to further the development of RET and potentially EGFR as therapeutic targets in breast cancer. Mechanisms regulating the expression of RET will be elucidated by examining the role of epigenetic chromatin modifications, co-factor interaction and post-translational modification of TFAP2C as potential mechanisms controlling RET expression in breast cancer. We will examine the cooperative effects of RET and EGFR mediating responsiveness to vandetanib in a panel of primary breast cancer isolates and establish a correlation between expression of RET and/or EGFR and vandetanib response as determined by ERK activation. To establish further clinical relevance, we propose an IRB-approved clinical trial utilizing a two- week preoperative therapy window with vandetanib to establish a correlation between RET expression and response to vandetanib as determined by changes in the surrogate molecular markers, Ki-67, CC3 and TUNEL. The overall impact of the studies will create a new paradigm in breast cancer directed therapy by establishing RET as a therapeutic target in breast cancer.

描述（由申请人提供）：TFAP2C/AP-2α 转录因子调节许多控制乳腺癌发生和进展的关键基因的表达。TFAP2C 基因位点的扩增在癌症中很常见，并且 TFAP2C 的过度表达与乳腺癌相关。 TFAP2C 调节雌激素受体 α (ERa) 相关基因的表达，包括编码受体的 RET 原癌基因。酪氨酸激酶 (RTK) 在 ERa 阳性管腔乳腺癌中更常见，我们最近的研究发现 RET 是乳腺癌的新治疗靶点，配体激活的 RET 通过激活包括 MAP 在内的多种信号通路来调节细胞生长。激酶/ERK 和 PI3 激酶/Akt 通路敲低 RET 表达或使用具有抗 RET 活性的酪氨酸激酶抑制剂 (TKI) 进行治疗，例如舒尼替尼或凡德他尼。诱导乳腺癌细胞凋亡，而抗雌激素会阻止增殖（通过 S 期或 Ki-67 测量），而抗 RET 治疗会诱导乳腺癌细胞凋亡（通过裂解的半胱天冬酶 3 (CC3) 或 TUNEL 测量），联合治疗会导致更大的细胞凋亡。此外，阻断 RET 活性可以增加抗雌激素的敏感性，并有可能诱导激素无反应乳腺癌的激素反应。依赖于 RET 表达，表明 RET 可用作预测 TKI 治疗反应的标志物。EGFR 的表达也受 TFAP2C 调节，最近的证据表明，在一些乳腺癌中，TKI 对 RET 和 EGFR 均具有活性。我们认为 RET 是乳腺癌治疗的新靶点；我们进一步认为 EGFR 可以与 RET 合作，共同靶向这些 RTK 可能会有效。我们建议进一步开发 RET 和潜在的 EGFR 作为乳腺癌治疗靶点，通过检查表观遗传染色质修饰、辅助因子相互作用和翻译后修饰的作用来阐明调节 RET 表达的机制。 TFAP2C 作为控制乳腺癌中 RET 表达的潜在机制我们将检查 RET 和 EGFR 在一组原发性乳腺癌分离株中介导凡德他尼反应的协同作用，并建立两者之间的相关性。通过 ERK 激活确定 RET 和/或 EGFR 的表达以及凡德他尼反应为了进一步建立临床相关性，我们建议进行一项经 IRB 批准的临床试验，利用凡德他尼的两周术前治疗窗口来建立 RET 表达和凡德他尼反应之间的相关性。通过替代分子标记物 Ki-67、CC3 和 TUNEL 的变化确定凡德他尼。这些研究的总体影响将通过将 RET 确立为治疗靶点，创建乳腺癌定向治疗的新范例。乳腺癌。