Repurposing RET Inhibitors for Endocrine Resistant Breast Cancer

项目总结/摘要 乳腺癌是最常见的癌症，也是癌症死亡的第二大常见原因。 妇女大多数乳腺癌是雌激素受体（ER）阳性。治疗失败的主要原因 ER+乳腺癌患者的死亡是对内分泌治疗（ET）的抵抗。新疗法 来改善耐药肿瘤患者的预后。一些研究结果表明， RET受体酪氨酸激酶改变对ET的敏感性。ER+乳腺癌中RET表达与 结果更差和对ET耐药的复发性肿瘤的RET表达水平高于 原发性肿瘤初步数据显示，RET在治疗的乳腺癌细胞中随着时间的推移而过度表达。 抑制RET可降低ERK/MAPK活性并使ER+细胞系和异种移植物敏感 到ET我们已经建立并验证了ER+乳腺癌类器官， RET表达增加的精确机制，RET如何影响对ET的敏感性，以及RET如何影响对ET的敏感性。 用ET治疗指导激酶信号传导。我们推测ET抵抗的RET高表达可能与ET抵抗的发生有关。 ER+乳腺癌驱动他莫昔芬耐药性，是克服耐药性的治疗靶点。到 为了验证这一假设，在Aim 1中，我们将定义RET启动子处调节元件的重编程 随着时间的推移，他莫昔芬导致RET的表达增加。在目标2中，我们将确定 靶向RET以增强细胞系、类器官和患者来源的异种移植物对ET的反应。 最后，在Aim 3中，我们将确定RET如何改变激酶信号适应对他莫昔芬的反应 使用与质谱联用的功能性抑制剂珠捕获测定。累积起来，这些 研究将为制定临床策略和选择RET抑制剂的患者提供科学依据 疗法除了促进科学知识，这项建议还提供了一个医生-科学家的培训。 Spanheimer博士是一位执业外科肿瘤学家，专门从事乳腺癌的分子背景研究。 生物学他的长期目标是联合收割机结合他的研究和临床专业知识， 受资助的研究计划，重点是改变基因调控的治疗脆弱性，以应对 疗法他受益于成熟的导师，他们在培训独立科学家方面有着良好的记录， 非常支持的研究环境。该建议书包括一个结构化的职业发展计划 和培训：1）转录调控的分子生物学，2）靶向治疗和预防 相关乳腺癌模型，和3）功能蛋白质组学。培训还将包括制定 在日益复杂的假设驱动的实验设计，执行和分析的专业知识。的 建议包括指导体验式学习，课程工作和会议参与，经常指导 会议和研究独立性的分级增加。这将累计确保在年底 获奖期间候选人已准备好领导一个独立的翻译研究计划。

PROJECT SUMMARY/ABSTRACT Breast cancer is the most common cancer and the second most common cause of cancer death in women. Most breast cancers are estrogen receptor (ER) positive. The primary cause of treatment failure and death in patients with ER+ breast cancer is resistance to endocrine therapy (ET). Novel therapeutics are needed to improve outcomes for patients with resistant tumors. Several findings demonstrate that the RET receptor tyrosine kinase alters sensitivity to ET. RET expression in ER+ breast cancer is associated with worse outcome and recurrent tumors that are resistant to ET express RET at higher levels than primary tumors. Preliminary data show that RET is overexpressed over time in breast cancer cells treated with ET and that inhibiting RET reduces ERK/MAPK activity and sensitizes ER+ cell lines and xenografts to ET. We have established and validated ER+ breast cancer organoids which we will use to dissect precise mechanisms of increased RET expression, how RET impacts sensitivity to ET, and how RET directs kinase signaling with ET treatment. We hypothesize that high expression of RET in ET resistant ER+ breast cancers drives tamoxifen resistance and is a therapeutic target to overcome resistance. To test this hypothesis, in Aim1 we will define reprogramming of regulatory elements at the RET promoter over time with tamoxifen leading to increased expression of RET. In Aim2, we will determine the efficacy of targeting RET to enhance response to ET in cell lines, organoids, and patient derived xenografts. Finally, in Aim3 we will determine how RET alters kinase signaling adaptation in response to tamoxifen using a functional inhibitor bead capture assay coupled with mass spectroscopy. Cumulatively, these studies will form a scientific basis to develop clinical strategies and select patients for RET inhibitor therapy. In addition to advancing scientific knowledge, this proposal provides training to a physician-scientist. Dr Spanheimer is a practicing surgical oncologist specializing in breast cancer with a background in molecular biology. His long-term goal is to combine his research and clinical expertise to develop an independently funded research program focused on therapeutic vulnerabilities of altered gene regulation in response to therapy. He benefits from established mentors with a strong track record of training independent scientists and an extremely supportive research environment. This proposal includes a structured career development plan and training in: 1) molecular biology of transcriptional regulation, 2) targeted therapeutics and translationally relevant breast cancer models, and 3) functional proteomics. Training will also include development of expertise in increasingly complex hypothesis driven experimental design, execution, and analysis. The proposal includes mentored experiential learning, course work and conference participation, frequent mentor meetings and a graded increase in research independence. Cumulatively, this will ensure at the end of the award period the candidate is ready to lead an independent translational research program.