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，也是癌症死亡的第二大原因 女性。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）的抗性。新颖的治疗学 需要改善耐药性肿瘤患者的预后。几个发现表明 RET受体酪氨酸激酶改变对ET的敏感性。 ER+乳腺癌中的RET表达与 较差的结果和反复发生的肿瘤，对ET Express RET具有较高水平的抗性 原发性肿瘤。初步数据表明，在治疗的乳腺癌细胞中，RET随着时间的流逝而过表达 ET和抑制RET可减少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，我们将用于剖析 RET表达增加的精确机制，RET如何影响对ET的敏感性以及RET的敏感性 通过ET处理指导激酶信号传导。我们假设RET在ET抗性中的高表达 ER+乳腺癌驱动了他莫昔芬的耐药性，是克服抗药性的治疗靶标。到 检验该假设，在AIM1中，我们将定义RET启动子的调节元素的重编程 随着时间的流逝，他莫昔芬会导致RET的表达增加。在AIM2中，我们将确定功效 靶向RET以增强细胞系，器官和患者衍生异种移植物中对ET的反应的靶向。 最后，在AIM3中，我们将确定RET如何改变对他莫昔芬的激酶信号的适应 使用功能性抑制剂珠捕获测定法与质谱法结合。累计，这些 研究将构成发展临床策略并为RET抑制剂选择患者的科学依据 治疗。除了促进科学知识外，该建议还向医师科学家提供培训。 Spanheimer博士是一名练习外科肿瘤学家，专门研究乳腺癌，具有分子背景 生物学。他的长期目标是结合他的研究和临床专业知识，以独立发展 基因调节改变基因调节的治疗脆弱性的资金研究计划， 治疗。他从成熟的导师中受益，并具有培训独立科学家的良好记录和 一个非常支持性的研究环境。该建议包括一个结构化的职业发展计划 和培训：1）转录调节的分子生物学，2）针对性的治疗和翻译 相关的乳腺癌模型和3）功能蛋白质组学。培训还将包括开发 越来越复杂的假设驱动实验设计，执行和分析方面的专业知识。这 建议包括指导的体验学习，课程工作和会议参与，经常导师 会议和研究独立性的分级提高。累积地，这将确保 奖励期候选人准备领导独立的翻译研究计划。