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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.

项目总结/文摘