Role of estrogen receptor-alpha in ovarian cancer

 描述（由申请人提供）：卵巢癌包括一组不同的恶性肿瘤，这些恶性肿瘤的检测和成功治疗具有挑战性。这种疾病往往不被发现，直到晚期，当它已经转移到整个腹腔。对疾病生物学及其分子异质性的有限理解阻碍了治疗的改进。根据患者的个体肿瘤生物学确定靶向治疗策略和分层治疗是改善临床结果的必要条件。 该项目的重点是了解雌激素受体α（ER α，为简单起见，在整个提案中称为ER）作为卵巢癌治疗靶点的潜力。ER是包括乳腺癌在内的几种癌症类型的既定驱动因素，靶向雌激素作用是ER阳性疾病乳腺癌患者的主要治疗策略。重要的是，ER在大多数（~80%）卵巢肿瘤中表达，流行病学证据支持雌激素在卵巢肿瘤发生中的作用。此外，临床试验表明，一部分卵巢癌患者可以通过内分泌治疗成功治疗。 为了确定ER在卵巢癌中的作用，我将利用分子生物学方法来确定哪些基因在体外和体内驱动ER介导的卵巢癌细胞的生长和存活。此外，我将在一个独特的、临床相关的卵巢癌小鼠模型中确定肿瘤生长是否需要雌激素。此外，我将在我们的小鼠模型中评估ER调节基因的表达，以确定这些基因是否可能是内分泌反应的潜在生物标志物。最后，我将测量这些假定的生物标志物在接受内分泌治疗的卵巢癌患者的临床标本中的表达，以确定表达是否与患者结局相关。 该提案的成功完成将建立卵巢癌中ER信号传导的机制，确定特定生物标志物是否与体内雌激素依赖相关，并确定特定基因的表达是否可用于预测对内分泌治疗的反应。确定内分泌治疗反应的预测性生物标志物将使临床医生能够前瞻性地确定将从内分泌治疗中受益的患者。 这种待遇。这些发现可能会刺激卵巢癌内分泌治疗的临床试验，并对卵巢癌治疗产生重大影响。

 DESCRIPTION (provided by applicant): Ovarian cancer comprises a diverse set of malignancies that are challenging to detect and to treat successfully. The disease often goes undetected until advanced stages, when it has metastasized throughout the abdominal cavity. Improvements in treatment have been hindered by limited understanding of the disease biology and its molecular heterogeneity. Identifying targeted therapeutic strategies and stratifying treatment based on a patient's individual tumor biology is sine qua non to improving clinical outcomes. This project focuses on understanding the potential of the estrogen receptor-alpha (ER, for simplicity called ER throughout the proposal) as a therapeutic target in ovarian cancer. ER is an established driver of several cancer types including breast cancer and targeting estrogen action is the primary therapeutic strategy for breast cancer patients with ER-positive disease. Importantly, ER is expressed in the majority (~80%) of ovarian tumors and epidemiologic evidence supports a role for estrogen in ovarian tumorigenesis. Moreover, clinical trials suggest a subset of ovarian cancer patients can be successfully treated with endocrine therapy. To determine the role of ER in ovarian cancer, I will utilize molecular biology approaches to identify what genes drive ER-mediated growth and survival in ovarian cancer cells in vitro and in vivo. Additionally, I will determine if estrogen is required for tumor growthin a unique, clinically relevant mouse model of ovarian cancer. Further, I will evaluate expression of ER-regulated genes in our mouse model to determine if these could be potential biomarkers of endocrine response. Finally, I will measure expression of these putative biomarkers in clinical specimens from ovarian cancer patients who received endocrine therapy to determine if expression correlates with patient outcome. Successful completion of this proposal will establish the mechanism of ER signaling in ovarian cancer, determine if specific biomarkers correlate with estrogen dependence in vivo, and determine if expression of specific genes can be used to predict response to endocrine therapy. Identifying predictive biomarkers for response to endocrine therapy will allow clinicians to prospectively identify patients who will benefit from this treatment. These findings may spur addition clinical trials of endocrine therapy in ovarian cancer and have significant ramifications for ovarian cancer treatment.