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：
8895506
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/8895506
关键词：
Animal Model Animals Automobile Driving Breast Cancer Cell Breast Cancer Patient Cell Culture System 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 Hormones Human Immunocompromised Host In Vitro Label Lead Malignant Neoplasms Mammary Neoplasms Measures Mediating Modeling Mus Neoplasm Metastasis Outcome Paraffin Embedding Pathology Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Play Primary Neoplasm Protein Kinase Protein Tyrosine Kinase Protein-Serine-Threonine Kinases Proteome Proteomics Qualifying Receptor Signaling Recruitment Activity Recurrence Refractory Research Personnel Resistance Resistance development Resolution Resources Role Sampling Signal Pathway Solid Somatotropin Specificity Specimen Staging Subfamily lentivirinae 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 novel novel therapeutics personalized medicine pre-clinical public health relevance response success targeted treatment therapeutic target 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.

描述（由申请人提供）：大约 70% 的乳腺癌表达雌激素受体 (ER) 虽然 ER 抑制剂（如他莫昔芬）挽救了数百万乳腺癌患者的生命，但约 40-50% 的乳腺癌患者出现了对他莫昔芬的耐药性。因此，开发针对激素难治性乳腺癌的新疗法以提高患者生存率的需求尚未得到满足，蛋白质是导致激素难治性的主要机制之一。激酶驱动的信号通路在病理上被激活，并规避了对 ER 信号传导的依赖。鉴于针对多种蛋白激酶的药物抑制剂的可用性，激酶已成为许多疾病特别是癌症中最有吸引力的治疗靶点。我们的发现将使用先进的高分辨率和高精度蛋白质组学方法来系统地识别在激素难治性乳腺癌中激活的新型蛋白激酶，以保持我们的研究与临床环境相关，而不是使用体外培养的细胞系。相反，我们将使用来自对激素治疗有不同反应的患者的乳腺肿瘤样本，我们将验证这些研究中发现的候选激酶在直接源自激素难治性转移性肿瘤的异种移植肿瘤中的治疗潜力。我们还将验证我们在乳腺癌肿瘤微阵列上的发现。 (TMA) 包含超过 800 个具有临床结果的乳腺癌肿瘤核心，该策略将帮助我们识别 ER 阳性乳腺癌中观察到的激素不应性所需的激酶，以缩短从实验室开始的路径。在临床方面，我们招募了一支高素质的多学科研究团队，能够最终将这些临床前发现转化为临床试验。研究的成功或拟议的研究不仅将识别具有治疗潜力的激酶，而且还为启动临床试验奠定了基础。 . 在激素难治性乳腺癌患者中测试有前景的药物。