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Personalized Therapy of Hormone Refractory Breast Cancer

激素难治性乳腺癌的个体化治疗

基本信息

批准号：
9247704
负责人：
AKHILESH PANDEY
金额：
$ 37.06万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247704
关键词：
Animal Model Animals Automobile Driving Breast Cancer Cell Breast Cancer Patient Cell Line Cessation of life Clinical Clinical Trials Correlative Study Data Dependence Development Disease Enrollment Estrogen Receptors Estrogen receptor positive Exhibits Foundations Freezing Future Goals Growth Growth Factor Hormone Responsive Hormones Human Immunocompromised Host In Vitro Label Lead Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Measures Mediating Modeling Mus Neoplasm Metastasis Outcome Paraffin Embedding Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phosphorylation Phosphotransferases Play Primary Neoplasm Protein Kinase Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proteome Proteomics Receptor Signaling Recruitment Activity Recurrence Refractory Research Personnel Resistance Resistance development Resolution Resources Role Sampling Signal Pathway Solid Somatotropin Specificity Specimen Subfamily lentivirinae System Tamoxifen Testing Therapeutic Time Tissue Microarray Tissues Translating Translations Tumor-Derived Tyrosine Universities Xenograft procedure base bench to bedside cell growth clinical application differential expression experience high risk hormone therapy improved in vivo inhibitor/antagonist malignant breast neoplasm medical schools multidisciplinary new therapeutic target novel novel therapeutics personalized medicine phosphoproteomics pre-clinical protein activation public health relevance response small hairpin RNA success targeted treatment therapeutic target three dimensional cell culture tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Approximately 70% of breast cancers express the estrogen receptor (ER). Although ER inhibitors such as tamoxifen have saved the lives of millions of breast cancer patients, development of resistance to tamoxifen occurs in ~40-50% patients receiving hormone therapy. Thus, there is an unmet need to develop novel therapies targeting hormone refractory breast cancers to improve patient survival. One of the major mechanisms of developing hormone refractoriness is protein kinase-driven signaling pathways becoming pathologically activated and circumventing the dependence on ER signaling. Given the availability of pharmacological inhibitors targeting a large spectrum of protein kinases, kinases have become most attractive therapeutic targets in many diseases particularly in cancer. In this proposed study, we will use advanced high- resolution and high-accuracy proteomic approaches to systematically identify novel protein kinases that are activated in hormone-refractory breast cancers. To keep our study relevant to the clinical setting, instead of using in vitro cultured cell lines, our discovery efforts will instead employ breast tumor samples from patients with different responses to hormonal therapy. We will validate the therapeutic potential of candidate kinases discovered in these studies in xenograft tumors directly derived from hormone refractory metastatic tumors. We will also validate our discoveries on breast cancer tumor microarrays (TMA) comprising >800 breast cancer tumor cores with clinical outcomes. This strategy will help us discern kinases that are required for hormone refractoriness observed in ER-positive breast cancer. In order to shorten the path from bench to bedside, we have recruited a highly qualified multidisciplinary team of investigators capable of ultimately translating these pre-clinical discoveries to clinical trials. A successful outcome of or proposed studies will not only identify kinases with therapeutic potential but also set the stage for initiating clinical trials to test promising drugs in patients with hormone refractory breast cancer.