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

UT

• 批准号: 9356787
• 负责人: ROBERT C BAST
• 金额: $ 173.29万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-22 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9356787
• 关键词: Achievement; Autoantibodies; Automobile Driving; BRCA1 Mutation; BRCA1 gene; BRCA2 gene; Biological Markers; Biology; Biopsy; Blood Vessels; CA-125 Antigen; CSF1R gene; Cancer Cell Growth; Cancer Center; Cancer Patient; Carboplatin; Caring; Cell Line; Cell Survival; Cell division; Centrosome; Chromatin; Clinic; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; DNA; DNA Repair; DNA Repair Disorder; DUSP6 protein; Data; Defect; Development; Diagnosis; Disease; Doctor of Medicine; Drug Targeting; Drug resistance; Early Diagnosis; Enzymes; Evaluation; Faculty; Failure; Funding; Generations; Genes; Germ-Line Mutation; Goals; Grant; Growth; HDAC5 gene; Individual; Interferons; International; Laboratories; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mediating; Mesenchymal Stem Cells; Mitosis; Molecular; Monitor; Moon; Mutation; Ovarian; PIK3CA gene; PTEN gene; Paclitaxel; Paper; Pathway interactions; Patient-Focused Outcomes; Patients; Peer Review; Pharmaceutical Preparations; Phase; Philanthropic Fund; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Platinum; Polyploidy; Predictive Value; Production; RNA; Recruitment Activity; Recurrence; Research Infrastructure; Research Personnel; Research Project Grants; Resistance; Retinoblastoma Protein; SERPINE1 gene; Serous; Services; Somatic Mutation; TP53 gene; Testing; Time; Translations; University of Texas M D Anderson Cancer Center; Wages; Woman; Xenograft procedure; angiogenesis; anticancer research; base; bevacizumab; biomarker identification; biomarker panel; cancer cell; cancer initiation; career; chemotherapy; design; docetaxel; homologous recombination; improved; improved outcome; inhibitor/antagonist; interest; knock-down; macrophage; malignant breast neoplasm; member; nanoassay; notch protein; novel; objective response rate; overexpression; peritoneal cancer; phase III trial; pre-clinical; preclinical study; predicting response; predictive marker; programs; protein biomarkers; resistance mechanism; response; response biomarker; screening; targeted agent; targeted treatment; tumor

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.

总体总结/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 为了通过组合基于分子的靶向剂来改善卵巢癌患者的结果， 他们的疾病的细胞和临床生物学以及对耐药性机制的理解和靶向。 在过去的6年里（2009 - 2015财年），MDACC已经照顾了4,483名卵巢、输卵管和卵巢癌患者。 腹膜癌MDACC通过招聘，工资和其他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。在过去的六年里，MDACC 招募了六名对卵巢癌研究感兴趣的杰出教职员工（AmirJazaeri博士， Larissa Meyer、Alpa Nick、Shannon Westin、Melinda Yates和Behrouz Zand）。慈善支助 妇女癌症乳腺-卵巢登月计划提供了组织和基础设施。在相同时间 在此期间，我们的前一个SPORE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SPORE研究人员贡献了461项同行评审 与卵巢癌相关的论文，53%（246）IF >5，20%（92）>10。取得的成就包括： 1)评估两阶段筛查策略，阳性预测值>30%，用于检测阶段 I-II疾病中9/12例被检测到; 2）鉴定生物标志物，其检测18%的CA 125阴性病例; 3)开发这些生物标志物的服务点纳米测定; 4）发现抗TP 53 自身抗体在CA 125之前5个月（中位数）-13个月（平均值）升高，CA 125是第一个提供早期诊断的生物标志物。 4）观察到抗血管生成治疗的客观反应率为54%， 阿柏西普和多西他赛; 5）启动靶向Dll 4和notch的试验; 6）CSF 1 R抑制剂可以消耗 7）证明MEK的显著活性 司美替尼抑制剂治疗低级别卵巢癌，并启动一项国际III期临床试验， 另一种有效的MEK抑制剂曲美替尼; 8）开发一种稳健的生物标志物面板，预测对 PARP抑制剂（PARPi）和启动PI 3 K和PARP抑制剂联合治疗高级别患者的多项试验 卵巢癌;和9）使用间充质干细胞向卵巢癌递送干扰素。这是新的 SPORE应用程序，4个项目将努力：1）验证预测生物标志物，并实施合理的 与PARP抑制剂的联合治疗，旨在克服预先存在的和适应性耐药性; 2） 验证预测性生物标志物，并与MEK抑制剂进行合理的联合治疗， 卵巢浆液性癌以克服耐药性; 3）靶向巨噬细胞以克服对抗VEGF的耐药性 4）在IA/B期试验中评价新的SIK 2抑制剂，并鉴定产生合成的SIK 2抑制剂的药剂。 杀伤力