Personalized Therapy of 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）。尽管ER抑制剂如他莫昔芬已经挽救了数百万乳腺癌患者的生命，但在接受激素治疗的患者中约有40-50%发生对他莫昔芬的耐药性。因此，开发靶向激素难治性乳腺癌的新疗法以改善患者存活率的需求尚未得到满足。发展激素不应性的主要机制之一是蛋白激酶驱动的信号传导途径被病理性激活并规避对ER信号传导的依赖。鉴于靶向广谱蛋白激酶的药理学抑制剂的可用性，激酶已成为许多疾病特别是癌症中最有吸引力的治疗靶标。在这项拟议的研究中，我们将使用先进的高分辨率和高准确度的蛋白质组学方法来系统地鉴定在乳腺癌难治性乳腺癌中被激活的新型蛋白激酶。为了使我们的研究与临床环境保持相关，我们的发现工作将采用来自对激素治疗有不同反应的患者的乳腺肿瘤样本，而不是使用体外培养的细胞系。我们将验证这些研究中发现的候选激酶在直接来源于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（TMA）上的发现，该微阵列包含>800个具有临床结果的乳腺癌肿瘤核心。这一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。为了缩短从实验室到临床的路径，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。一个成功的结果或拟议的研究不仅将确定具有治疗潜力的激酶，而且还为启动临床试验奠定了基础，以测试激素难治性乳腺癌患者有希望的药物。

 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.