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

基本信息

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
项目类别：
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

项目摘要

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.

总体摘要/摘要德克萨斯大学医学博士安德森癌症中心（MDACC）卵巢癌孢子的总体目标是通过根据分子组合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耐药性的理解和靶向机制。在过去的6年中（2009年至2015财年），MDACC照顾了4,483例卵巢，输卵管和腹膜癌。 MDACC通过招募，薪水对卵巢癌研究高度重视支持，临床设施，实验室空间和慈善基金。在过去的6年中，MDACC有招募了对卵巢癌研究感兴趣的六名杰出教职员工（Amir Jazaeri博士， Larissa Meyer，Alpa Nick，Shannon Westin，Melinda Yates和Behrouz Zand）。慈善支持妇女癌症乳房伏安的月球射击提供了组织和基础设施。同时时期，我们以前的孢子资助了15个发展研究项目（DRP），并支持了六个职业增强计划（CEP）获奖者和孢子调查人员已贡献了461个同行评审与卵巢癌有关的论文为53％（246），如果> 5和20％（92）> 10。成就包括： 1）评估检测阶段的阳性预测值> 30％的两阶段筛选策略 I-II疾病在发现的12例中有9例； 2）鉴定检测CA125阴性病例18％的生物标志物； 3）开发这些生物标志物的服务点纳米测定； 4）发现抗TP53 自身抗体在CA125之前上升5（中位数）-13个月（平均），这是第一个提供的生物标志物检测比CA125; 4）观察对抗血管生成治疗的54％客观反应率 Aflibercept和Docetaxel； 5）针对DLL4和Notch的试验的倡议； 6）CSF1R抑制剂可能缺少巨噬细胞并降低对抗VEGF治疗的耐药性7）表明MEK显着活性低级卵巢癌的抑制剂selumetinib和国际III期试验的倡议另一个有效的MEK抑制剂Trametinib； 8）开发强大的生物标志物面板，该面板预测了对 PARP抑制剂（PARPI）和组合PI3K和PARP抑制剂的多个试验的倡议卵巢癌； 9）使用间质干细胞向卵巢癌提供干扰。我是新的孢子应用程序，4个项目将努力：1）验证预测生物标志物并实施理性与PARP抑制剂的组合疗法旨在克服预先抗性和适应性抗性； 2）验证预测性生物标志物并使用MEK抑制剂实施合理组合疗法卵巢浆液癌以克服抗药性； 3）目标巨噬细胞克服对抗VEGF的抗性疗法； 4）在IA/B期试验中评估一种新型的SIK2抑制剂，并确定产生合成的药物致死性。