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

• 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
• 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

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安德森癌症中心卵巢癌SPORE的总体目标是测试和翻译小说 治疗策略，包括克服对常规细胞毒性药物的适应性耐药性的治疗策略， 化疗、聚（ADP-核糖）聚合酶抑制剂（PARPi）、抗血管生成剂（贝伐单抗） 和免疫检查点阻断。在过去的五年里，1,417名新的卵巢癌患者接受了 在MD安德森的护理。我们通过招聘，工资支持， 临床设施、实验室空间和慈善基金。来自MD安德森的慈善支持 卵巢癌月球拍摄提供了组织和基础设施，但在孢子的工作是 完全不同我们成功地实施了增加征聘妇女的措施， 代表性不足的少数民族到我们的发展研究计划（DRP）和职业提升 程序（CEP）。在过去的22年里，我们的SPORE研究人员贡献了1280多份手稿 在过去的四年里有155人死于卵巢癌。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%的病例在I期或II期被检测到; 2）确定了检测18%的CA 125的生物标志物 阴性病例; 3）开发了一种4-生物标志物算法，可追溯检测晚期疾病 1.4比基于CA 125的NROSS算法早4.8年; 4）发现抗TP 53自身抗体 CA 125前8个月和诊断前22个月升高; 5）观察到54%的客观缓解 使用阿柏西普和多西他赛进行抗血管生成治疗的比率; 6）完成了靶向Dll 4的试验; 7） 证明CSF 1 R抑制剂可以消耗巨噬细胞并降低抗VEGF的抗性 治疗; 8）证明MEK抑制剂司美替尼在低级别卵巢癌中具有显著活性 并完成了另一种强效MEK抑制剂曲美替尼的国际III期试验; 9）开发了 一个稳健的生物标志物组，可预测PARPi的应答和启动多项PI 3 K联合试验 和PARPi治疗高级别卵巢癌。在拟定的SPORE、项目1和项目4研究者中， 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 以加快进展并改善卵巢癌妇女的预后。这两个项目都有潜力 增强肿瘤中的T细胞浸润并赋予免疫记忆，这在考虑到 癌症复发的可能性在项目2中，我们将开发一种新的靶向TR 0 P2的CAR-NK疗法。 在项目3中，我们将开发针对肿瘤微环境的治疗方法，使用一种新的EGFL 6靶向 单克隆抗体总的来说，我们的翻译研究是在一个最佳的环境中进行的， 机构团队致力于改善卵巢癌妇女临床结果。