Repurposing RET Inhibitors for Endocrine Resistant Breast Cancer

重新利用 RET 抑制剂治疗内分泌耐药乳腺癌

• 批准号: 10644068
• 负责人: PHILIP M SPANHEIMER
• 金额: $ 20.3万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644068
• 关键词: Active Learning; Acute; Address; Award; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer Model; Cancer Etiology; Cancer Model; Cause of Death; Cell Line; Cessation of life; Chromatin; Chronic; Clinical; Clinical Trials; Complex; Coupled; DNA Binding; Data; Development; Development Plans; Disease; Dose; ERBB2 gene; Endocrine; Enhancers; Ensure; Environment; Epigenetic Process; Estrogen Receptors; Estrogen receptor positive; Experimental Designs; Funding; Future; Gene Expression Regulation; Genetic Transcription; Goals; Growth; Human; K-Series Research Career Programs; Knowledge; Lead; MAP Kinase Gene; MCF7 cell; Malignant Neoplasms; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Mentors; Methylation; Modeling; Modification; Molecular Biology; Molecular Genetics; Organoids; Outcome; Patient Selection; Patient-Focused Outcomes; Patients; Phosphotransferases; Physicians; Primary Neoplasm; Proliferating; Promoter Regions; Proteomics; Protocols documentation; RET inhibition; Recurrent tumor; Regulatory Element; Research; Research Personnel; Resistance; Role; Scientific Advances and Accomplishments; Scientist; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Structure; Sulfides; Surgical Oncologist; T47D; TFAP2C gene; Tamoxifen; Testing; Therapeutic; Therapeutic Uses; Time; Training; Transcriptional Regulation; Treatment Failure; Woman; Work; Xenograft Model; Xenograft procedure; biomarker identification; career development; chromatin immunoprecipitation; effective therapy; efficacy evaluation; glial cell-line derived neurotrophic factor; hormone therapy; improved outcome; in vivo; inhibitor; inhibitor therapy; knock-down; malignant breast neoplasm; meetings; novel therapeutics; overexpression; patient derived xenograft model; preclinical efficacy; programs; promoter; proteogenomics; proto-oncogene protein c-ret; receptor; receptor binding; response; response biomarker; symposium; targeted treatment; therapeutic target; therapy resistant; translational model; translational research program; treatment response; tumor; tumor growth

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.

项目摘要/摘要 乳腺癌是最常见的癌症，也是#年癌症死亡的第二大常见原因。 女人。大多数乳腺癌是雌激素受体(ER)阳性的。治疗失败的主要原因 ER阳性乳腺癌患者的死亡是内分泌治疗(ET)的抵抗。新疗法 是改善耐药肿瘤患者预后所必需的。几项研究结果表明， RET受体酪氨酸激酶改变对ET的敏感性。RET在ER+乳腺癌中的表达 预后较差和对ET耐药的复发肿瘤表达RET的水平高于 原发肿瘤。初步数据显示，随着时间的推移，RET在接受治疗的乳腺癌细胞中过度表达 抑制RET可降低ERK/MAPK活性并使ER+细胞株和异种移植瘤增敏 致ET。我们已经建立并验证了ER+乳腺癌有机体，我们将用它来解剖 RET表达增加的确切机制，RET如何影响对ET的敏感性，以及RET如何 指导ET治疗中的信号转导。我们推测RET在ET耐药中的高表达 ER+乳腺癌导致他莫昔芬耐药，是克服耐药的治疗靶点。至 验证这一假设，在Aim1中，我们将定义RET启动子调控元件的重新编程 随着时间的推移，三苯氧胺导致RET表达增加。在AIM2中，我们将确定疗效 靶向RET以增强细胞系、器官和患者来源的异种移植中对ET的反应。 最后，在Aim3中，我们将确定RET如何改变他莫昔芬对激酶信号的适应 使用功能性抑制物珠捕获分析与质谱学相结合。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 心理治疗。除了提高科学知识外，这项建议还为内科科学家提供培训。 斯潘海默博士是一名执业外科肿瘤学家，专门研究乳腺癌，具有分子背景。 生物学。他的长期目标是将他的研究和临床专业知识结合起来，独立开发一种 资助的研究计划专注于改变基因调控对治疗的脆弱性 心理治疗。他受益于在培训独立科学家和 极具支持性的研究环境。该提案包括一项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)靶向治疗和翻译 相关乳腺癌模型；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下的实验设计、执行和分析方面的专业知识。这个 建议书包括有指导的体验式学习、课程作业和参与会议、经常指导 会议和研究独立性的逐步提高。累积起来，这将确保在 获奖期候选人已准备好领导一个独立的翻译研究项目。