HCC Ovarian Cancer SPORE

HCC 卵巢癌孢子

• 批准号: 10713050
• 负责人: Ronald J Buckanovich
• 金额: $ 216.38万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713050
• 关键词: Address; Advocate; American; Archives; BRCA1 gene; Bioinformatics; Biometry; Bromodomains and extra-terminal domain inhibitor; Cancer Center; Cancer Etiology; Cancer Patient; Carboplatin; Cell Cycle Checkpoint; Cell Cycle Checkpoint Genes; Cells; Cessation of life; Chemoresistance; Clinical; Clinical Data; Clinical Trials; Collaborations; Cost Sharing; DNA Repair; Development; Diagnosis; Disease; Disease Progression; Disease Resistance; Doctor of Philosophy; Dose; EZH2 gene; Ensure; Epigenetic Process; Erinaceidae; Exclusion; Experimental Models; Funding; Future; Generations; Goals; Human; Immune; Immune checkpoint inhibitor; Immunotherapy; In Vitro; Incidence; Individual; Institution; Investments; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mesenchymal Stem Cells; Minority Groups; Mitotic; Modeling; Molecular; Myeloid-derived suppressor cells; New Agents; Newly Diagnosed; Operative Surgical Procedures; Pathology; Patient Care; Patient-Focused Outcomes; Patients; Pennsylvania; Phase; Phase Ib Trial; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Positioning Attribute; Prediction of Response to Therapy; Principal Investigator; Prognosis; Program Research Project Grants; Proteins; Recurrence; Relapse; Research; Research Infrastructure; Research Personnel; Resistance; Resource Sharing; Science; Scientist; Signal Transduction; TOPBP1 Gene; Technology; Testing; Time; Translational Research; Underrepresented Minority; Woman; anticancer research; cancer care; career; career development; checkpoint therapy; chemotherapy; data resource; design; experience; homologous recombination; improved; improved outcome; in vivo; inhibitor; inhibitor therapy; innovation; mortality; multidisciplinary; multipotent stromal progenitor; notch protein; novel diagnostics; novel therapeutic intervention; novel therapeutics; patient response; personalized medicine; phase II trial; potential biomarker; pre-clinical; prevent; programs; recruit; response; smoothened signaling pathway; stem cells; stromal progenitor; success; synergism; therapeutic development; therapy resistant; tissue resource; treatment strategy; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT – OVERALL Ovarian cancer (OvCa) has the third highest mortality to incidence ratio and is the fifth leading cause of cancer death in American women. The typical disease course of a patient with OvCa spans four and a half years from the time of diagnosis to death. During the course of patient care, acquired and innate resistance to our most effective and promising therapies, such as chemotherapy, PARP inhibitor therapy, and immunotherapy, drives disease progression. The overall goal of the UPMC Hillman Cancer Center (HCC) OvCa SPORE is to prevent and/or overcome therapeutic resistance to improve patient survival. Each of the SPORE’s three Projects evolved from the innovative concepts and findings of SPORE investigators. Each project involves a clinical trial with a new agent. In addition, each project, through complementary investigator expertise, incorporates critical translational aims to identify patients most likely to respond to therapy. Project 1 will assess the ability of inhibitors of the epigenetic regulator EZH2 to prevent/overcome OvCa stromal progenitor cell-driven resistance to platinum-based chemotherapy. Project 2 will determine whether BET inhibitors, which downregulate critical DNA repair and cell cycle checkpoint proteins, can reverse resistance to PARP inhibitors. Project 3 will test whether inhibitors of the hedgehog signaling pathway, which drives tumor immune exclusion, can improve OvCa patient response to immune checkpoint inhibitor therapy. The HCC OvCa SPORE will include a Career Enhancement Program (CEP) and Developmental Research Program (DRP) in order to both encourage early career investigators to enter the field of translational OvCa research and engage more established investigators in OvCa research. The CEP and the DRP, which are cost-shared and proactive at providing research funding to investigators from under-represented minority groups, will provide a pipeline of potential future SPORE Projects. All SPORE, CEP, and DRP Projects will be receive fiscal and scientific oversight from an Administrative Core and support from two shared resource cores. The Translational Pathology Core will collect, annotate, archive, and distribute biospecimens and clinical data derived from the more than 300 HCC OvCa patients seen each year. It will also develop new preclinical experimental models that behave more like human OvCa. The Biostatistics and Bioinformatics Core will aid in design and analysis of all studies, including ‘omic’ technologies that can provide molecular and spatial characterization of individual cells within a tumor. The SPORE Projects will also be supported by established and new collaborators who are internal and external to HCC. Combined, the SPORE projects, CEP, DRP, and cores are positioned, together with our vertical collaborators, to improve the outcomes of patients with ovarian cancer. The findings generated by the SPORE will be advanced through further collaboration and future non-SPORE funding.

项目总结/摘要-总体 卵巢癌（OvCa）的死亡率与发病率之比排名第三，是癌症的第五大病因 美国女性的死亡OvCa患者的典型病程跨越四年半， 从确诊到死亡。在病人护理过程中，后天和先天的抵抗力，我们最 有效和有前途的治疗，如化疗，PARP抑制剂治疗和免疫治疗， 疾病进展。UPMC希尔曼癌症中心（HCC）OvCa孢子的总体目标是预防 和/或克服治疗抗性以提高患者存活率。SPORE的三个项目 从SPORE研究人员的创新概念和发现演变而来。每个项目都涉及临床试验 一个新的经纪人。此外，每个项目都通过互补的调查员专门知识， 翻译的目的是确定最有可能对治疗产生反应的患者。项目1将评估 表观遗传调节剂EZH 2的抑制剂，以预防/克服OvCa基质祖细胞驱动的抗性 到铂类化疗。项目2将确定是否BET抑制剂，下调关键 DNA修复和细胞周期检查点蛋白，可以逆转对PARP抑制剂的耐药性。项目3将测试 hedgehog信号通路的抑制剂是否可以改善肿瘤免疫排斥， OvCa患者对免疫检查点抑制剂治疗的反应。HCC OvCa SPORE将包括职业生涯 增强计划（CEP）和发展研究计划（DRP），以鼓励早期 职业调查人员进入翻译OvCa研究领域，并从事更成熟的 OvCa研究的研究人员。CEP和DRP分摊费用并主动提供 研究资金，以调查人员从代表不足的少数群体，将提供一个管道， 未来的项目。所有的SPORE、CEP和DRP项目都将接受以下机构的财政和科学监督： 一个管理核心和来自两个共享资源核心的支持。转化病理学核心将 收集、注释、存档和分发来自300多个HCC的生物标本和临床数据 每年都有OvCa患者。它还将开发新的临床前实验模型， 人OvCa。生物统计学和生物信息学核心将有助于设计和分析所有研究，包括 “组学”技术可以提供肿瘤内单个细胞的分子和空间表征。 SPORE项目还将得到内部和新的合作者的支持， 在HCC之外。结合，SPORE项目，CEP，DRP和核心定位，以及我们的 垂直合作者，以改善卵巢癌患者的预后。调查结果显示， SPORE将通过进一步的合作和未来的非SPORE资金来推进。