Novel Biomarkers in Ovarian Cancer

描述(由申请人提供)：在美国2008年约24,000例新的上皮性卵巢癌病例中，晚期卵巢癌占大多数(&gt；75%)。每年有超过16,000人死亡，使这种癌症成为最致命的妇科恶性肿瘤。然而，只有少数生物标志物可以用来预测卵巢癌患者的总体生存时间。此外，许多预后生物标记物最终可以作为重要的治疗靶点，如果他们的分子作用被很好地理解的话。利用转录图谱技术结合COX回归分析，我们先前已经确定了一个假定的基因特征，它可以预测晚期高级别浆液性卵巢癌患者的生存。在签名中COX分数最高的基因被称为微纤维相关糖蛋白(MAGP-2)，已被证明与含有纤维蛋白的微纤维相关，并与成纤维细胞中的1V23整合素特异地相互作用。然而，它在肿瘤发病机制中的作用还没有被探讨。我们的初步研究表明，卵巢肿瘤组织标本中MAGP-2的表达与患者的生存显著相关。此外，MAGP-2还能诱导高表达1V23整合素的人脐静脉内皮细胞和卵巢癌细胞的生长和运动。此外，外源MAGP-2可显著诱导HUVECs和卵巢癌细胞株OVCA429的钙离子振荡和FAK磷酸化。因此，我们假设高水平表达MAGP-2的卵巢癌细胞通过其与1V23整合素的相互作用调节卵巢癌的生长，从而导致卵巢癌患者总体生存率较低。在这一应用中，我们建议使用大量的多中心临床试验标本进一步验证MAGP-2的预后价值，并阐明MAGP-2在卵巢发病机制中的功能作用。首先，我们将使用从加入妇科肿瘤组(GOG)方案218的患者获得的样本，将MAGP-2的表达与结果相关联。其次，我们将描述MAGP-2在体内外调控卵巢肿瘤生长和进展中的功能作用。最后，我们将描绘MAGP-2在卵巢癌细胞和内皮细胞中诱导细胞增殖、迁移和侵袭的信号网络。这项拟议的研究如果成功，将为我们提供一个新的卵巢癌预后生物标志物。它将引导我们寻找新的治疗靶点，开发新的卵巢癌治疗方案。 公共卫生相关性：这项拨款建议使用从随机III期试验中前瞻性收集的样本来验证MAGP-2作为晚期卵巢癌预后生物标记物的有效性。将进行机制研究，以了解MAGP2在卵巢癌生长中的作用机制。

DESCRIPTION (provided by applicant): Advanced stage ovarian cancer accounts for the majority (>75%) of the approximately 24,000 new cases of epithelial ovarian cancer in year 2008 in the United States. Over 16,000 deaths per year occur, making this cancer the most lethal gynecologic malignancy. However, there are only a few biomarkers that can be used to predict overall ovarian cancer patient survival. In addition, many prognostic biomarkers can ultimately serve as important therapeutic targets if their molecular action is well understood. Using transcriptional profiling technology combined with Cox regression analysis, we have previously identified a putative gene signature, which can predict survival in patients with advanced stage high-grade serous ovarian cancers. The gene with highest Cox score in the signature is called microfibril-associated glycoprotein (MAGP-2), which has been shown to be associated with fibrillin-containing microfibrils and to interact specifically with 1V23 integrin in fibroblasts. However, its role in cancer pathogenesis has not been explored. Our preliminary studies demonstrated that MAGP-2 expression in ovarian tumor tissues samples significantly correlated with patient survival. In addition, MAGP-2 was shown to induce cell growth and motility in both human umbilical vein endothelial cells (HUVECs) and ovarian cancer cells, which expressed high levels of 1V23 integrin. Furthermore, exogenous MAGP-2 was shown to significantly induce Ca2+ oscillation and FAK phosphorylation in HUVECs and an ovarian cancer cell line OVCA429. We therefore hypothesize that ovarian cancer cells expressing high levels of MAGP-2 modulate ovarian cancer growth and through its interaction with 1V23 integrin, which subsequently leads to poorer overall ovarian cancer patient survival. In this application, we proposed to further validate the prognostic value of MAGP-2 using a large collection of multi-center clinical trial specimens, and delineate the functional role of MAGP-2 in ovarian pathogenesis. First, we will correlate MAGP-2 expression with outcomes using specimens obtained from patients entered into the Gynecologic Oncology Group (GOG) protocol 218. Second, we will delineate the functional role of MAGP-2 in modulating ovarian tumor growth and progression, in vitro and in vivo. Finally, we will delineate the signaling network for MAGP-2-induced cell proliferation, migration and invasion in both ovarian cancer cells and endothelial cells. This proposed study if successful will provide us with a new prognostic biomarker for ovarian cancer. It will lead us to the identification of new therapeutic targets and the development of new therapeutic regimens for ovarian cancer treatment. PUBLIC HEALTH RELEVANCE: This grant proposes to validate MAGP-2 as a prognostic biomarker for advanced stage ovarian cancer using prospectively collected specimens from a randomized phase III trial. Mechanistic studies will be performed to understand the mechanisms of action of MAGP2 in ovarian cancer growth.