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

项目SuIVIMARY(请参阅说明)： 晚期低级别卵巢浆液性癌约占晚期卵巢浆液性癌的10% 卵巢浆液性癌分期。而患有这种疾病的患者的5年存活率显著 与高级别口腔鳞癌相比，大多数低级别口腔鳞状细胞癌患者最终会死于 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，低级别的口腔鳞癌是一种 这是一种独特的疾病，对标准化疗不太敏感。尽管在组织学和 临床结果，低级别或高级别口腔鳞癌患者目前正在接受治疗，其中 对低级别的OSC并不是很有效。因此，新的治疗策略和新的分子靶点正在 迫切需要改善这一患者队列的结果。最近的研究表明， 在低级别口腔鳞癌中，由于激活了KRAS/BRAF，MAPK通路主要被激活 突变或其他未知机制表明，靶向MAP激酶途径的分子 前景看好的疗法。在与妇科肿瘤学小组的合作下，我们最近启动了一个阶段 II期临床试验(GOG 0239)，靶向活化的MAPK通路治疗复发性低级别口腔鳞癌 MEK抑制剂AZD6244作为单药。初步分析显示，一些项目取得了令人满意的结果 初步数据分析中的应答者。此外，利用微阵列技术对显微解剖的肿瘤进行分析 样本中，我们发现IGF1-AKT通路主要在低级别口腔鳞癌中激活。此外， 我们最近发现FOXOSa是PI3K/AKT、MEK/ERK、IKK信号转导的共同靶点，其 AZD6244在低级别卵巢癌细胞中的定位和表达可能是AZD6244敏感性的预测因子。 根据这些研究的结果，我们假设在体内激活了多条信号通路 低级别OSC，以及通过综合基因组和蛋白质组分析鉴定的分子标记 对通路靶向抑制剂的应答者和无应答者的比例可用于预测药物反应和 对患者进行分层，以便将来进行通路靶向方案的临床试验。为了检验这些假设，我们建议 (1)确定MEK抑制剂AZD6244抗肿瘤效果的基因组和蛋白质组预测因子 GOG0239标本；(2)研究FOXOSa在诱导抗药性中的功能作用 低分化卵巢癌细胞中Pisk/AKT和MEK/ERK的表达；(3)IGF1-P1SK的研究 途径作为治疗低级别口腔鳞癌的潜在靶点；以及(4)开发涉及新的临床试验 联合靶向代理方法。我们相信，我们的学习将帮助我们发展个性化 对于患有低级别口腔鳞癌的女性，采用毒性较低、疗效较高的治疗方案。

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.