Integration of Predictive Biomarkers of Hormone Resistance in Breast Cancer

描述(申请人提供)：患有雌激素受体(ER)阳性乳腺癌的妇女接受针对ER的激素类药物治疗，并可保持多年的无病状态。然而，治疗最终会产生抗药性，因此这些妇女将遭受癌症复发的痛苦。在我们目前的授权期内，我们探讨了我们的建议，即 这些女性成功治疗的关键是专注于识别新的耐药机制，使用对激素治疗耐药的转移性肿瘤，在这些肿瘤中，已经发生了肿瘤进化和耐药克隆选择。利用这种创新的方法，我们已经发现了几种新的个体耐药机制，包括两种关键的抗性负调控因子-Rho鸟嘌呤解离抑制因子α(Rho GDIa)和生长因子受体支架蛋白SLC9A3R1的水平降低，这两种机制都通过ERA的磷酸化来增强Era的激活。我们将重点研究这两种耐药机制，并确定它们对具有野生型ERA的细胞以及我们首次在乳腺肿瘤中发现的两种特定ERA突变(赖氨酸303和酪氨酸537)的影响，这两种突变显著影响激素反应。我们将利用这些耐药机制来对耐药肿瘤的生长施加更精确的控制，结合激素和靶向治疗以及对关键ERA生长通路的激活状态的了解。因此，我们现在建议验证与Rho GDIa或SLC9A3R1缺失相关的特定耐药机制及其对ERA的影响，以针对这些特定机制，并将这些发现转化为准确的预测临床生物标志物和潜在的治疗靶点。我们的目标是：(1)针对SLC9A3R1和Rho GDIa耐药机制，以恢复激素敏感性和对靶向治疗的反应；(2)确定SLC9A3R1和Rho GDIa耐药通路如何影响突变ERA功能；以及(3)利用我们广泛的回顾性临床乳腺肿瘤资源，验证这两种途径中选定的候选通路预测激素和生物疗法耐药的能力。这项工作应该会为大量ER阳性乳腺癌患者带来广泛有效的复发抑制，尽管继续进行内分泌治疗，但她们现在每天都担心自己的疾病复发。

DESCRIPTION (provided by applicant): Women with estrogen receptor (ER)-positive breast cancer are treated with hormonal agents targeting the ER, and can remain free of disease for many years. However, resistance to treatment eventually develops, and these women will thus suffer a recurrence of their cancer. In our current grant period, we explored our proposal that the key to the successful treatment of these women is to focus on identifying novel mechanisms of resistance, using metastatic tumors resistant to hormone therapy in which tumor evolution and clonal selection for resistance have already occurred. Using this innovative approach, we have already discovered several new individual resistance mechanisms, including reduced levels of two key negative regulators of resistance - Rho guanine dissociation inhibitor alpha (Rho GDIa) and the growth factor receptor scaffolding protein SLC9A3R1, both of which enhance activation of ERa via its phosphorylation. We will focus on these two resistance mechanisms, and determine their effect on cells with wild-type ERa as well as two specific ERa mutations (lysine 303 and tyrosine 537) that we were the first to discover in breast tumors, and which significantly affect hormone response. We will exploit these resistance mechanisms to exert more precise control over resistant tumor growth, combining hormonal and targeted therapy along with knowledge of the activation status of the key ERa growth pathway. Therefore, we now propose to validate specific resistance mechanisms associated with losses of Rho GDIa or SLC9A3R1 and their effects on ERa, to target these specific mechanisms, and to translate these findings to pinpoint predictive clinical biomarkers and potential treatment targets. Our Aims are: (1) To target SLC9A3R1 and Rho GDIa resistance mechanisms to restore hormone sensitivity and response to targeted therapies; (2) To determine how SLC9A3R1 and Rho GDIa.resistance pathways pact on mutant ERa function; and (3) To validate selected candidates from these two pathways for their ability to predict resistance to targeted hormone and biologic therapies, using our extensive retrospective clinical breast tumor resources. This work should lead to extended effective suppression of recurrence for the large numbers of women with ER-positive breast cancer who now daily fear reappearance of their disease in spite of continued endocrine treatment.