The University of Texas MD Anderson Cancer Center SPORE in Ovarian Cancer

德克萨斯大学 MD 安德森癌症中心 SPORE 在卵巢癌中的应用

基本信息

批准号：
10709227
负责人：
ROBERT C BAST
金额：
$ 214.41万
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：
2023
资助国家：
美国
起止时间：
2023-09-19 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709227
关键词：
Affect Algorithms Angiogenesis Inhibitors Autoantibodies Biological Markers Biology Biopsy Blood Vessels CA-125 Antigen CSF1R gene Cancer Center Cancer Patient Carboplatin Caring Cell Therapy Clinical Clinical Trials Combined Modality Therapy Cytotoxic Chemotherapy Development Diagnosis Disease Drug Targeting Drug resistance EGF-Like Domain EGFL6 gene EP300 gene Early Detection Research Network Environment Epidermal Growth Factor Exhibits Future Goals Histologic Human Immune checkpoint inhibitor Immunologic Memory Infrastructure Institution International Laboratories MEKs Macrophage Malignant Neoplasms Malignant neoplasm of ovary Manuscripts Measures Molecular Monoclonal Antibodies Moon Morbidity - disease rate Natural Killer Cell toxicity Natural Killer Cells Outcome Ovarian PIK3CG gene Paclitaxel Patient-Focused Outcomes Patients Pharmaceutical Preparations Philanthropic Fund Phosphotransferases Poly(ADP-ribose) Polymerase Inhibitor Progression-Free Survivals Recurrence Relapse Research Research Design Research Personnel Resistance Resistance development Risk Signal Transduction Sodium Chloride Speed Surface Antigens T cell infiltration TP53 gene Testing Therapeutic Monoclonal Antibodies Time Translating Tumor Angiogenesis Underrepresented Minority University of Texas M D Anderson Cancer Center Vascular Endothelial Growth Factors Wages Woman Work angiogenesis anticancer research bevacizumab biomarker identification biomarker panel cancer cell career conventional therapy docetaxel effective therapy efficacy testing humanized monoclonal antibodies immune checkpoint blockade immune checkpoint blockers improved improved outcome inhibitor innovation mortality novel novel therapeutic intervention novel therapeutics objective response rate patient subsets phase III trial preclinical study predicting response pressure programs recruit resistance mechanism response screening targeted agent therapy development therapy resistant translational study treatment strategy trophoblast tumor tumor microenvironment wound healing

项目摘要

The overall goal of the MD Anderson Cancer Center SPORE in Ovarian Cancer is to test and translate novel therapeutic strategies, including those to overcome adaptive resistance to conventional cytotoxic chemotherapy, poly (ADP-ribose) polymerase inhibitors (PARPi), anti-angiogenic agents (bevacizumab) and immune checkpoint blockade. Over the last five years, 1,417 new patients with ovarian cancer received care at MD Anderson. We have prioritized ovarian cancer research through recruitment, salary support, clinical facilities, laboratory space, and philanthropic funds. Philanthropic support from the MD Anderson Ovarian Cancer Moon Shot has provided organization and infrastructure, but the work in the SPORE is completely distinct. We successfully implemented measures to increase the recruitment of women and underrepresented minorities to our Developmental Research Program (DRP) and Career Enhancement Program (CEP). Over the last 22 years, our SPORE investigators have contributed over 1280 manuscripts regarding ovarian cancer with 155 in the last four years. Our SPORE has made significant contributions including: 1) conducted the SPORE and EDRN-supported Normal Risk Ovarian Screening Study (NROSS) where 71% of cases have been detected in stage I or II; 2) identified biomarkers that detect 18% of CA125 negative cases; 3) developed a 4-biomarker algorithm that in retrospect detects advanced stage disease 1.4 to 4.8 years earlier than the CA125-based NROSS algorithm; 4) found anti-TP53 autoantibodies elevated 8 months before CA125 and 22 months before diagnosis; 5) observed a 54% objective response rate to anti-angiogenic therapy with aflibercept and docetaxel; 6) completed a trial targeting Dll4; 7) demonstrated that CSF1R inhibitors can deplete macrophages and reduce resistance to anti-VEGF therapy; 8) demonstrated significant activity of the MEK inhibitor selumetinib in low-grade ovarian cancers and completed an international phase III trial of another potent MEK inhibitor trametinib; and 9) developed a robust biomarker panel that predicts response to PARPi and initiation of multiple trials combining PI3K and PARPi in high-grade ovarian cancer. In the proposed SPORE, Project 1 and Project 4 investigators tackle therapeutic resistance to PARP inhibitors and immune checkpoint blockers from multiple directions to speed progress and improve outcomes for women with ovarian cancer. Both projects have the potential to enhance T-cell infiltration in tumors and impart immunologic memory, which is particularly important given the likelihood of this cancer to recur. In Project 2, we will develop a novel TROP2-targeted CAR-NK therapy. In Project 3, we will develop therapy aimed at the tumor microenvironment using a novel EGFL6 targeted monoclonal antibody. Overall, our translational studies conducted in an optimal environment with a multi- institutional team are directed toward improving clinical outcomes of women with ovarian cancer.

MD 安德森癌症中心 SPORE 在卵巢癌方面的总体目标是测试和转化新颖的卵巢癌药物。治疗策略，包括克服对传统细胞毒性的适应性耐药性的策略化疗、聚（ADP-核糖）聚合酶抑制剂（PARPi）、抗血管生成剂（贝伐珠单抗）和免疫检查点封锁。过去 5 年，1,417 名新卵巢癌患者接受了治疗 MD 安德森中心的护理。我们通过招聘、薪资支持、临床设施、实验室空间和慈善基金。 MD 安德森癌症中心的慈善支持卵巢癌登月计划提供了组织和基础设施，但 SPORE 的工作是完全不同。我们成功实施了增加女性招聘的措施发展研究计划 (DRP) 和职业提升中代表性不足的少数群体计划（CEP）。在过去 22 年里，我们的 SPORE 调查员贡献了超过 1280 份手稿过去四年中，有 155 例卵巢癌患者。我们的SPORE做出了重大贡献包括：1) 进行了 SPORE 和 EDRN 支持的正常风险卵巢筛查研究 (NROSS) 其中 71% 的病例是在第一或第二阶段发现的； 2) 鉴定出可检测 18% CA125 的生物标志物负面案例； 3) 开发了一种 4 生物标志物算法，可以回顾性地检测晚期疾病比基于CA125的NROSS算法早1.4~4.8年； 4）发现抗TP53自身抗体 CA125前8个月和诊断前22个月升高； 5) 观察到 54% 的客观反应阿柏西普和多西他赛抗血管生成治疗的比率； 6) 完成了针对Dll4的试验； 7）证明 CSF1R 抑制剂可以消耗巨噬细胞并降低对抗 VEGF 的抵抗治疗; 8) 证明 MEK 抑制剂 Selumetinib 在低级别卵巢癌中具有显着活性并完成了另一种强效 MEK 抑制剂曲美替尼 (Trametinib) 的国际 III 期试验； 9) 开发一个强大的生物标志物组，可预测 PARPi 的反应并启动结合 PI3K 的多项试验和 PARPi 在高级别卵巢癌中的作用。在拟议的 SPORE 中，项目 1 和项目 4 的研究人员从多个方向解决对 PARP 抑制剂和免疫检查点阻断剂的治疗耐药性加快进展并改善卵巢癌女性的治疗结果。两个项目都有潜力增强肿瘤中 T 细胞的浸润并赋予免疫记忆，这一点尤其重要这种癌症复发的可能性。在项目2中，我们将开发一种新型的TROP2靶向CAR-NK疗法。在项目 3 中，我们将使用一种新型 EGFL6 靶向药物来开发针对肿瘤微环境的治疗方法。单克隆抗体。总的来说，我们的转化研究是在一个具有多种因素的最佳环境中进行的。机构团队致力于改善卵巢癌女性的临床结果。