Vitamin D and Ovarian Cancer Prevention and Treatment

描述(申请人提供)：卵巢癌是妇科恶性肿瘤的主要死亡原因，它对目前的治疗反应不佳，需要开发新的治疗或预防策略来对抗这种致命的疾病。我们的研究表明，多个卵巢癌细胞系对1，25VD的生长抑制有反应。机制研究表明，1，25VD抑制生长因子信号转导，诱导细胞周期停滞，促进细胞凋亡。多种肿瘤抑制基因和癌基因被鉴定为受1，25VD调节，以介导这些肿瘤抑制活性。更重要的是，体外和体内研究都表明，合成的1.25VD类似物EB1089是一种有前途的药物，可用于预防和治疗卵巢癌。基于这些发现，我们认为1.25VD通过核维生素D受体的转录活性在卵巢癌细胞中发挥肿瘤抑制作用，通过诱导抑癌基因的表达和抑制癌基因的表达，导致细胞周期停滞在G1/S和G2/M检查点以及细胞凋亡。我们认为，低钙合成的VD类似物不仅是卵巢癌一级预防的有用药物，而且WIU也为卵巢癌患者提供了一种新的治疗方法。本研究旨在通过实现以下三个具体目标来证实这一假说：目的1.验证1，25VD通过转录下调表皮生长因子受体抑制细胞对血清生长因子的反应，从而将卵巢癌细胞周期阻滞在G1/S检查点的概念：目的2：验证1.25VD诱导卵巢癌细胞G2/M期阻滞和凋亡是通过诱导GADD45偶联的概念，并确定GADD45下游调节1，25VD的两个独立活性的步骤，重点是p38，Bcl2和Calain的作用；目的3.整合来自分子研究的信息，并利用机制信息，指导我们努力推进EB1089用于卵巢癌的临床治疗。我们相信，我们的研究解决了一个正在研究的领域，并可能导致EB1089作为治疗卵巢癌的新型治疗或化学预防药物的开发。此外，我们的研究对1，25VD的作用机制有了许多新的发现，这可能会对卵巢癌以外的人产生更广泛的影响。

DESCRIPTION (provided by applicant): Ovarian cancer is the leading cause of death among gynecological malignancies and its poor response to current treatments necessitates the development of novel therapeutic or preventive strategies to fight against this deadly disease. Our studies showed that multiple ovarian cancer cell lines responded to 1,25VD for growth suppression. Mechanistic studies suggest that 1,25VD suppresses growth factor signaling, induces cell cycle arrest and promotes apoptosis. Multiple tumor suppressors and oncogenes were identified as being regulated by 1,25VD to mediate these tumor-suppressing activities. More importantly, both in vitro and in vivo studies suggested that synthetic 1.25VD analog EB1089 is a promising drug that can be used to prevent and treat ovarian cancer. Based on these findings, we propose that 1.25VD, through the transcriptional activity of the nuclear vitamin D receptor (VDR), exert a tumor suppressing pathway in ovarian cancer cells; by inducing the expression of tumor suppressors and inhibiting the expression of oncogenes, leading to cell cycle arrest at G1/S and G2/M checkpoints as well as apoptosis. We believe that less calcemic synthetic VD analogues are not only useful drugs for the primary prevention of ovarian cancer, but wiU also premise ovarian cancer patients a new method of treatment. The proposed studies are to substantiate this hypothesis by achieving the following three specific aims: Aim 1. To test the concept that 1,25VD arrests ovarian cancer cell cycle progression at G1/S checkpoint by inhibiting the cells' response to serum growth factors through the transcriptional down-regulation of the epidermal growth factor receptor; Aim 2:To test the concept that the G2/M arrest and apoptosis induced by 1.25VD in ovarian cancer cells are coupled through the induction of GADD45 and to define the steps downstream of GADD45 that mediates the two separale activities of 1,25VD with a focus on the role of p38, Bcl-2 and calpain; Aim 3. To integrate the information from the molecular studies and, using the mechanistic information, to guide our effort to advance EB1089 for clinical management of ovarian cancer. We believe our studies address an area of research that is under studied and may lead to the development of EB1089 as a novel therapeutic or chemo-preventive drug to treat ovarian cancer. In addition, our studies made many novel findings about the mechanism of 1,25VD action, which may have a much broad impact beyond ovarian cancer.