NOVEL STRATEGIES FOR OVARIAN CANCER PREVENTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 卵巢表面上皮(OSE)是大多数女性卵巢癌的来源，但仅占卵巢的不到1/1000。人们对OSE转化的基础知之甚少，阻碍了改进治疗策略的发展。由于晚期卵巢癌的预后显著下降(I期治愈率95%，但IV期5年生存率仅为10%)，预防和早期发现策略可能是减少卵巢癌死亡人数的最大希望。我们正在开发两种预防卵巢癌的新策略：第一，我们寻求完全消除OSE，使用洗涤剂和轻度擦伤(上皮切除)；第二，我们希望使用组蛋白去乙酰酶抑制剂Vorinostat来调节OSE中FANCD2的表达。FANCD2介导DNA修复，并在培养的OSE细胞中减少，这些细胞来自有卵巢癌家族史的女性。此外，这些细胞还表现出组蛋白3乙酰化降低，这可能减少FANCD2的表达。我们将在体内确定Vorinostat是否上调组蛋白3乙酰化和FANCD2的表达。这个项目更广泛地寻求建立一个研究计划，通过对健康、有风险和癌症患者的OSE细胞进行微阵列和分子分析，将确定OSE转化的关键因素。非人灵长类动物系统将被用于评估这些元素作为治疗操作的候选元素，并将数据转化为卵巢癌预防和早期检测治疗的临床应用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ovarian surface epithelium (OSE) is the source of most ovarian cancers in women, yet comprises less than 1/1,000th of the ovary. The basis for OSE transformation is poorly understood, hindering the development of improved strategies for treatment. Since the prognosis for ovarian cancer declines dramatically when the disease is diagnosed at later stages (95% cure rate at stage I, but a 5-year survival rate of only 10% at stage IV), strategies for prevention and early detection may offer the best hope of reducing the number of fatalities from ovarian cancer. We are developing two novel strategies for ovarian cancer prevention: first, we seek to eliminate the OSE completely, using detergent and mild abrasion (epitheliectomy); second, we wish to modulate FANCD2 expression in the OSE using the histone deacetylase inhibitor Vorinostat. FANCD2 mediates DNA repair, and is reduced in cultured OSE cells derived from women with a family history of ovarian cancer. In addition, these cells also exhibit decreased Histone 3 acetylation, which may reduce FANCD2 expression. We will determine whether Vorinostat elevates Histone 3 acetylation and FANCD2 expression in vivo. This project more broadly seeks to establish a research program whereby microarray and molecular analysis of OSE cells from healthy, at risk, and cancer patients will identify key elements in OSE transformation. The nonhuman primate system will be used to evaluate these elements as candidates for therapeutic manipulation, and the data will be translated into clinical application for ovarian cancer prevention and early detection therapies.