Mayo Clinic Ovarian Cancer SPORE

项目概要-总体 卵巢癌（OC）马约诊所SPORE的修订申请建立在转化研究的基础上， 在6-10年的资助期间进行。我们在过去五年取得的成就包括：i） 独特的疫苗策略，在一项I期研究中，在高级别患者中，49个月时无复发生存率为39%， 浆液性OC，ii）对限制PARP作用的基因组和生化变化的新认识 抑制剂（PARPis）在OC中的分布，iii）超过9600份用于OC研究的生物标本，iv）220份 用品.发展研究方案为这次更新的四个项目中的两个项目作出了贡献; 和职业提升计划（CEP）有助于领导两个项目。的总体目标 SPORE仍然支持创新、互动、转化的OC研究，利用基础知识的专业知识 IC和翻译研究人员。这次更新包含四个翻译项目，旨在调查OC 生物学和增强治疗反应，建立在最近的临床进展和有希望的临床前结果的基础上： · P1（用于OC的Th 17诱导树突状细胞[DC]疫苗的开发）：基于我们的研究显示， 用叶酸受体α肽脉冲并成熟为Th 17诱导表型的DC诱导免疫再分化， 在所有患者中的sponses和39%的长期无复发生存率，我们将确定长期无复发生存率的决定因素。 II期试验中长期疫苗应答并阐明该疫苗的免疫逃逸机制。 · P2（用于治疗OC的下一代TOP1抑制剂）：基于我们观察到TOP1抑制剂b- TOR在PARPi抗性OC模型中是有活性的，并且这种活性可以通过PARPi治疗来增强，即使在 面对PARPi耐药性，该项目将确定对TOP1抑制剂/PARPi敏感性的决定因素 组合，并进行超长效TOP1 i PLX 038与PARPi rucaparib的II期试验。 · P3（将色瑞替尼重新用于OC治疗）：基于发现色瑞替尼，一种用于ALK的激酶抑制剂， 重排的肺癌，抑制线粒体呼吸，增加活性氧， OC细胞系和PDX对PARP的作用不依赖于ALK状态，我们将确定介导这些作用的途径。 进行ceritinib/olaparib联合治疗的I期试验。 P4（使用基因编辑的CAR NK细胞治疗晚期OC）：建立在先前的发展研究基础上 这个位于明尼苏达大学的团队将应用先进的细胞工程技术， 产生具有增强的肿瘤归巢和持久性的活化NK细胞，然后测试安全性和有效性 在铂类耐药OC的I期临床试验中给予这种同种异体过继免疫疗法。 这些有影响力的项目由四个高度互动的核心支持：核心A（行政），核心B（Biospec- imens/患者登记）、核心C（生物统计学/生物信息学）和核心D（动物模型）。DRP和CEP将 用于培养下一代的翻译OC调查员。总的来说，这些SPORE活动将 提供了新的见解OC生物学，同时检查这种致命疾病的潜在治疗进展。

PROJECT SUMMARY – OVERALL This revised application of the Mayo Clinic SPORE in Ovarian Cancer (OC) builds on translational research con- ducted during Years 6-10 of funding. Our accomplishments over the past five years include i) identification of a unique vaccine strategy that, in a phase I study, led to 39% recurrence free survival at 49 months in high grade serous OC, ii) new understanding of the genomic and biochemical changes that limit the action of PARP inhibitors (PARPis) in OC, iii) distribution of over 9600 biospecimens for OC research, and iv) publication of 220 articles. The Developmental Research Program (DRP) has contributed to two of the four projects in this renewal; and the Career Enhancement Program (CEP) contributed to leadership of two projects. The overall goal of the SPORE remains to support innovative, interactive, translational OC research that leverages the expertise of bas- ic and translational investigators. This renewal contains four translational projects designed to investigate OC biology and enhance therapeutic response, building on recent clinical advances and promising preclinical results: • P1 (Development of a Th17-Inducing Dendritic Cell [DC] Vaccine for OC): Based on our study showing that DCs pulsed with Folate Receptor α peptides and matured to a Th17-inducing phenotype induced immune re- sponses in all patients and long-term recurrence-free survival in 39%, we will identify determinants of long- term vaccine response in a phase II trial and elucidate mechanisms of immune escape from this vaccine. · P2 (Next Generation TOP1 Inhibition for the Treatment of OC): Building on our observation that TOP1 inhib- itors are active in PARPi-resistant OC models and this activity can be enhanced by PARPi treatment even in the face of PARPi resistance, this project will identify determinants of sensitivity to TOP1 inhibitor/PARPi combinations and conduct a phase II trial of the ultra-long acting TOP1i PLX038 with the PARPi rucaparib. · P3 (Repurposing Ceritinib for OC Therapy): Based on the finding that ceritinib, a kinase inhibitor used for ALK- rearranged lung cancer, inhibits mitochondrial respiration, increases reactive oxygen species, and sensitizes OC cell lines and PDXs to PARPis independent of ALK status, we will identify pathways that mediate these effects and conduct a phase I trial of the ceritinib/olaparib combination. · P4 (Treatment of Advanced OC Using Gene-Edited CAR NK Cells): Building on a prior developmental research project, this team located at the University of Minnesota will apply advanced cellular engineering techniques to generate activated NK cells with enhanced tumor homing and persistence, then test the safety and efficacy of administering this allogeneic adoptive immunotherapy in a phase I clinical trial in platinum-resistant OC. These impactful projects are supported by four highly interactive cores: Core A (Administrative), Core B (Biospec- imens/Patient Registry), Core C (Biostatistics/Bioinformatics) and Core D (Animal Models). A DRP and CEP will be used to nurture the next generation of translational OC investigators. Collectively, these SPORE activities will provide new insight into OC biology while examining potential therapeutic advances for this lethal disease.