P3 - Personalized Therapy for Low-Grade Serous Carcinoma of the Ovary

项目随附资料（见说明）： 晚期低级别卵巢浆液性癌（OSC）约占所有晚期卵巢浆液性癌的10%。 卵巢浆液性癌分期。虽然患者的5年生存率显著高于 高级别的OSC患者，大多数低级别的OSC患者最终死于 疾病最近的遗传学和基因组研究表明，低级别OSC和高级别OSC具有 不同的致病途径。此外，最近的临床证据表明，低级别的OSC是一种 独特的疾病，对标准化疗不太敏感。尽管在组织学和 临床结果，低级别或高级别OSC患者目前接受治疗， 在低等级OSC中并不有效。因此，新的治疗策略和新的分子靶点被发现。 迫切需要改善这一患者队列的结果。最近的研究表明， 由于激活KRAS/BRAF，MAP激酶途径主要在低级别OSC中被激活 突变或其他未知的机制，表明靶向MAP激酶途径的分子是 有前途的治疗方法与妇科肿瘤组合作，我们最近启动了一个阶段， II期临床试验（GOG 0239），使用 MEK抑制剂AZD 6244作为单药。初步分析表明，一些有希望的结果， 在初始数据分析中的响应。此外，使用微阵列分析显微切割的肿瘤， 样本中，我们发现IGF 1-AKT通路的激活主要发生在低级别OSC中。此外，委员会认为， 我们最近发现FOXOSa是PI 3 K/AKT、MEK/ERK、IKK信号传导的共同靶点， 定位和表达可能是低级别卵巢癌细胞中AZD 6244敏感性的预测因子。 基于这些研究的结果，我们假设，多个信号通路被激活， 低级别OSC，以及通过全面的基因组和蛋白质组学分析鉴定的分子标记物 对通路靶向抑制剂的应答者和非应答者的比率可用于预测药物应答， 对患者进行分层，以便将来进行通路靶向治疗方案临床试验。为了验证这些假设，我们建议 (1)为了鉴定MEK抑制剂AZD 6244的抗肿瘤功效的基因组和蛋白质组学预测因子， GOG 0239标本;（2）研究FOXOSa在赋予抑制剂抗性中的功能作用 PISK/AKT和MEK/ERK激酶在低级别卵巢癌细胞中的表达;（3）研究IGF 1-P1 SK 作为低级别OSC的潜在治疗靶点;以及（4）开发涉及新的 联合靶向药物方法。我们相信，我们的研究将有助于我们发展个性化的 治疗方案，将有较低的毒性和较高的疗效，为妇女与低级别的OSC。

PROJECT SUIVIMARY (See instructions): Advanced stage low-grade ovarian serous cancer (OSC) represents approximately 10% of all advanced stage ovarian serous carcinomas. While the 5-year survival rates of patients with the disease is significantly higher than those with high-grade OSC, most patients with low-grade OSC eventually succumb to their disease. Recent genetic and genomic studies have shown that low-grade OSC and high-grade OSC have different pathogenetic pathways. Furthermore, recent clinical evidence has indicated that low-grade OSC is a unique disease and is less sensitive to standard chemotherapy. In spite of differences in histology and clinical outcomes, patients with low-grade or high-grade OSC are currently treated with the treatments, which are not that effective in low-grade OSC. Thus, new therapeutic strategies and novel molecular targets are desperately needed to improve the outcome of this patient cohort. Recent studies have demonstrated that the MAP kinase pathway is activated predominately in low-grade OSC because of activating KRAS/BRAF mutations or other unknown mechanisms suggesting that molecules targeting the MAP kinase pathway are promising therapeutics. In collaboration with the Gynecologic Oncology Group, we recently initiated a phase II clinical trial (GOG 0239) targeting the activated MAP kinase pathway in recurrent low-grade OSC using the MEK inhibitor, AZD6244, as a single agent. Preliminary analysis showed promising results with a number of responders in an initial data analysis. In addition, using microarray analysis on microdissected tumor samples, we identified activation of the IGF1-AKT pathway predominately in low-grade OSC. Furthermore, we recently showed that FOXOSa is a common target of PI3K/AKT, MEK/ERK, IKK signaling, and its localization and expression may be a predictor for AZD6244 sensitivity in low-grade ovarian cancer cells. Based on the results from these studies, we hypothesize that multiple signaling pathways are activated in low-grade OSC, and molecular markers identified through comprehensive genomic and proteomic analyses of responders and non-responders to pathway-targeted inhibitors can be used to predict drug responses and stratify patients for future clinical trials of pathway-targeted regimens. To test these hypotheses, we propose (1) to identify genomic and proteomic predictors of anti-tumor efficacy of the MEK inhibitor AZD6244 using GOG 0239 specimens; (2) to investigate the functional role of FOXOSa in conferring resistance to inhibitors of PISK/AKT and MEK/ERK kinases in low-grade ovarian cancer cells; (3) to investigate the IGF1-P1SK pathway as a potential therapeutic target for low-grade OSC; and (4) to develop clinical trials involving novel combined targeted agent approaches. We believe that our studies will help us to develop individualized treatment regimens that will have lower toxicity and higher efficacy, for women with low-grade OSC.