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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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女性。大多数乳腺癌呈雌激素受体 (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。新疗法需要改善耐药肿瘤患者的治疗结果。多项研究结果表明 RET 受体酪氨酸激酶改变对 ET 的敏感性。 ER+ 乳腺癌中的 RET 表达相关与 ET 相比，结果更差且复发的肿瘤对 ET 具有更高的 RET 表达水平原发性肿瘤。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与 ET 结合，抑制 RET 会降低 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，我们将用它来解剖 RET 表达增加的精确机制、RET 如何影响对 ET 的敏感性以及 RET 如何通过 ET 治疗指导激酶信号传导。我们假设 ET 耐药性中 RET 高表达 ER+乳腺癌会导致他莫昔芬耐药，是克服耐药性的治疗靶点。到检验这个假设，在 Aim1 中，我们将定义 RET 启动子处调控元件的重编程随着时间的推移，他莫昔芬导致 RET 表达增加。在Aim2中，我们将确定功效靶向 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 Aim3 中，我们将确定 RET 如何改变激酶信号适应以响应他莫昔芬使用功能性抑制剂珠捕获测定结合质谱法。累计起来，这些研究将为制定临床策略和选择接受 RET 抑制剂的患者奠定科学基础治疗。除了提高科学知识之外，该提案还为医师科学家提供培训。 Spanheimer 博士是一位执业肿瘤外科医师，专门研究乳腺癌，具有分子生物学背景生物学。他的长期目标是结合他的研究和临床专业知识，独立开发一种资助的研究计划侧重于改变基因调控的治疗脆弱性，以应对治疗。他受益于在培训独立科学家方面拥有良好记录的知名导师和一个极其支持的研究环境。该提案包括结构化的职业发展计划以及以下方面的培训：1) 转录调控的分子生物学，2) 靶向治疗和转化相关乳腺癌模型，3) 功能蛋白质组学。培训还将包括开发日益复杂的假设驱动的实验设计、执行和分析方面的专业知识。这提案包括指导式体验式学习、课程作业和会议参与、经常导师会议和研究独立性的逐步提高。累积起来，这将确保在年底奖励期间，候选人已准备好领导一个独立的转化研究项目。