Integration of Predictive Biomarkers of Hormone Resistance in Breast Cancer

描述（由申请人提供）：患有雌激素受体（ER）阳性乳腺癌的女性用靶向ER的激素药物治疗，并且可以多年保持无疾病。然而，对治疗的抵抗最终会发展，这些妇女将因此遭受癌症复发。在我们目前的赠款期间，我们探讨了我们的建议， 成功治疗这些妇女的关键是集中精力确定新的耐药机制，使用对激素治疗具有耐药性的转移性肿瘤，其中已经发生了肿瘤进化和耐药性克隆选择。使用这种创新方法，我们已经发现了几种新的个体抗性机制，包括降低两种关键的抗性负调节因子- Rho鸟嘌呤解离抑制剂α（Rho GDIa）和生长因子受体支架蛋白SLC 9A 3R 1的水平，这两种蛋白都通过其磷酸化增强ER α的激活。我们将专注于这两种耐药机制，并确定它们对野生型ER α细胞的影响，以及我们在乳腺肿瘤中首次发现的两种特异性ER α突变（赖氨酸303和酪氨酸537），这些突变显著影响激素反应。我们将利用这些耐药机制来更精确地控制耐药肿瘤的生长，结合激素和靶向治疗沿着关键ER α生长途径的激活状态。 因此，我们现在提出验证与Rho GDIa或SLC 9A 3R 1丢失相关的特异性耐药机制及其对ER α的影响，靶向这些特异性机制，并将这些发现转化为精确的预测性临床生物标志物和潜在的治疗靶点。我们的目标是：（1）靶向SLC 9A 3R 1和Rho GDIa抗性机制，以恢复激素敏感性和对靶向治疗的反应;（2）确定SLC 9A 3R 1和Rho GDIa抗性途径如何影响突变型ER a功能;和（3）使用我们广泛的回顾性临床乳腺肿瘤资源，验证从这两种途径中选择的候选物预测对靶向激素和生物疗法的抗性的能力。 这项工作应导致扩大有效的抑制复发的大量妇女ER阳性乳腺癌谁现在每天都害怕复发的疾病，尽管继续内分泌治疗。

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.