U.T. M. D. Anderson Cancer Center SPORE in Ovarian Cancer

总体摘要/摘要 德克萨斯大学MD安德森癌症中心(MDACC)卵巢癌孢子的总体目标是 为了通过结合基于分子的靶向药物来改善卵巢癌患者的预后， 其疾病的细胞和临床生物学以及对耐药的理解和靶向机制。 在过去的6年中(2009财年至2015财年)，MDACC已经护理了4483名卵巢、输卵管和 腹膜癌。MDACC通过招聘、薪酬等方式高度重视卵巢癌研究 支持、临床设施、实验室空间和慈善基金。在过去的6年里，MDACC已经 招聘了六名对卵巢癌研究感兴趣的优秀教职员工(Amir Jazeri博士， 拉丽莎·迈耶、阿尔帕·尼克、香农·威斯汀、梅琳达·耶茨和贝鲁兹·赞德)。慈善事业的支持 女性癌症乳房-卵巢登月提供了组织和基础设施。在同一时间内 在此期间，我们以前的孢子资助了15个发展研究项目(DRP)，并支持了6个职业 增强计划(CEP)获奖者和孢子调查人员贡献了461项同行评审 与卵巢癌相关的论文占53%(246篇)和20%(92篇)和10篇。成果包括： 1)对两阶段筛查策略的评价，其阳性预测值为30% I-II病9例：2)CA125阴性病例中18%检测到生物标记物； 3)这些生物标记物的服务点纳米分析的发展；4)发现抗TP53 自身抗体比CA125早5个月(中位数)-13个月(平均)，CA125是更早提供的第一个生物标志物 比CA125检测；4)观察抗血管生成治疗54%的客观有效率 AfLibercept和多西紫杉醇；5)启动针对DLL4和Noch的试验；6)CSF1R抑制剂可能耗尽 巨噬细胞和降低对抗血管内皮生长因子治疗的抵抗力7)MEK显著活性的证明 赛鲁米替尼在低级别卵巢癌中的应用及其国际III期临床试验的启动 另一种有效的MEK抑制剂曲美替尼；8)开发一种强大的生物标志物小组，可预测对 PARP抑制剂(PARPI)和联合PI3K和PARP抑制剂治疗高级别癌症的多项试验的启动 卵巢癌；以及9)使用间充质干细胞向卵巢癌输送干扰素。我是S新 孢子应用，4个项目将努力：1)验证预测生物标志物并实施Rational 与PARP抑制剂联合治疗，旨在克服预先存在的和适应性耐药；2) 验证预测生物标志物并与MEK抑制剂合理联合治疗低度恶性淋巴瘤 卵巢浆液性癌克服耐药性；3)靶向巨噬细胞克服对抗血管内皮生长因子的耐药性 治疗；以及4)在IA/B期试验中评估一种新的SIK2抑制剂并确定产生合成SIK2抑制剂的药物 杀伤力。

Overall SUMMARY/ABSTRACT The overall goal of the University of Texas MD Anderson Cancer Center (MDACC) Ovarian Cancer SPORE is to improve outcomes for ovarian cancer patients by combining targeted agents based upon the molecular, cellular and clinical biology of their disease and understanding and targeting mechanisms of drug resistance. Over the last 6 years (FY2009-FY2015), MDACC has cared for 4,483 patients with ovarian, fallopian tube and peritoneal cancers. MDACC has given high priority to ovarian cancer research through recruitment, salary support, clinical facilities, laboratory space, and philanthropic funds. Over the last 6 years, MDACC has recruited six outstanding faculty members with an interest in ovarian cancer research (Drs. Amir Jazaeri, Larissa Meyer, Alpa Nick, Shannon Westin, Melinda Yates, and Behrouz Zand). Philanthropic support of the Women’s Cancer Breast-Ovarian Moon Shot has provided organization and infrastructure. Over the same time period, our previous SPORE funded 15 Developmental Research Projects (DRPs), and supported six Career Enhancement Program (CEP) awardees, and SPORE investigators have contributed 461 peer-reviewed papers pertaining to ovarian cancer with 53% (246) IF >5 and 20% (92) >10. Achievements included: 1) evaluation of a two stage screening strategy with a positive predictive value of >30% for detecting stage I-II disease in 9 of 12 cases detected; 2) identification of biomarkers that detect 18% of CA125 negative cases; 3) development of a point-of-service nanoassay for these biomarkers; 4) discovery that anti-TP53 autoantibodies rise 5 (median) -13 months (mean) prior to CA125, the first biomarker to provide earlier detection than CA125; 4) observation of a 54% objective response rate to anti-angiogenic therapy with aflibercept and docetaxel; 5) initiation of a trial targeting Dll4 and notch; 6 ) CSF1R inhibitors could deplete macrophages and reduce resistance to anti-VEGF Therapy 7) demonstration of significant activity of the MEK inhibitor selumetinib in low-grade ovarian cancers and initiation of an international phase III trial of another potent MEK inhibitor trametinib; 8) development of a robust biomarker panel that predicts response to PARP inhibitors (PARPi) and initiation of multiple trials combining PI3K and PARP inhibitors in high-grade ovarian cancer; and 9) use of mesenchymal stem cells to deliver interferon to ovarian cancers. I n t h i s new SPORE application, 4 projects will strive to: 1) validate predictive biomarkers and implement rational combination therapy with PARP inhibitors designed to overcome pre- existing and adaptive resistance; 2) validate predictive biomarkers and implement rational combination therapy with MEK inhibitor for low-grade ovarian serous cancers to overcome resistance; 3) target macrophages to overcome resistance to anti-VEGF therapies; and 4) evaluate a novel SIK2 inhibitor in a Phase IA/B trial and identify agents that produce synthetic lethality.