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

基本信息

批准号：
10005257
负责人：
ROBERT C BAST
金额：
$ 172.29万
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/10005257
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 Infrastructure Interferons International Laboratories MEKs 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 Phase Ia/Ib Trial Philanthropic Fund Phosphorylation Phosphorylation Inhibition Phosphotransferases Platinum Polyploidy Predictive Value Production RNA Recurrence Research Personnel Research Project Grants Resistance Retinoblastoma Protein SERPINE1 gene Serous Services Somatic Mutation TP53 gene Testing Time Translations Tumor-associated macrophages 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 recruit 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.

总体总结/摘要德克萨斯大学 MD 安德森癌症中心 (MDACC) 卵巢癌 SPORE 的总体目标是通过结合基于分子、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 6 年（2009 财年至 2015 财年）中，MDACC 已治疗了 4,483 名卵巢、输卵管和卵巢癌患者。 MDACC 通过招聘、薪资等方式高度重视卵巢癌研究。在过去 6 年里，MDACC 获得了支持、临床设施、实验室空间和慈善基金。招募了六名对卵巢癌研究感兴趣的杰出教员（Amir Jazaeri 博士， Larissa Meyer、Alpa Nick、Shannon Westin、Melinda Yates 和 Behrouz Zand）的慈善支持。女性癌症乳腺癌卵巢登月计划同时提供了组织和基础设施。在此期间，我们之前的 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 份经过同行评审的论文与卵巢癌相关的论文，IF > 5 为 53% (246)，IF > 20% (92) > 10。 1) 评估两阶段筛查策略，检测阶段的阳性预测值 >30% 12 例中的 9 例检测到 I-II 疾病；2) 鉴定出检测到 18% CA125 阴性病例的生物标志物； 3) 开发针对这些生物标志物的服务点纳米测定法；4) 发现抗 TP53；自身抗体比 CA125 早 5（中位数）-13 个月（平均值）上升，CA125 是第一个更早提供的生物标志物检测结果优于 CA125；4) 观察到抗血管生成治疗的客观缓解率为 54% 阿柏西普和多西紫杉醇；5) 启动针对 Dll4 和 notch 的试验；6) CSF1R 抑制剂可能会耗尽巨噬细胞并降低抗 VEGF 疗法的抵抗力 7) 证明 MEK 具有显着活性抑制剂塞美替尼治疗低级别卵巢癌并启动国际 III 期试验另一种有效的 MEK 抑制剂曲美替尼 (trametinib)；8) 开发一个强大的生物标志物组来预测对药物的反应 PARP 抑制剂 (PARPi) 以及启动 PI3K 和 PARP 抑制剂联合用于高级别药物的多项试验卵巢癌；9) 使用间充质干细胞向卵巢癌输送干扰素。 SPORE应用，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 抑制剂联合治疗，旨在克服预先存在的适应性耐药性 2) 验证预测生物标志物并与 MEK 抑制剂实施合理的低级别联合治疗卵巢浆液性癌克服耐药性3)靶向巨噬细胞克服抗VEGF的耐药性疗法；4) 在 IA/B 期试验中评估一种新型 SIK2 抑制剂，并鉴定产生合成药物的药物杀伤力。