Dana Farber/Harvard Cancer Center Ovarian Cancer SPORE grant

项目概要（总体） 卵巢癌孢子应用程序的总体部分描述了背景， 三个项目四个核心的具体目标、创新点和研究计划。我们强调内部- SPORE合作和开发伴随生物标志物的临床试验。通过这个孢子 应用，我们试图解决卵巢癌治疗中几个最紧迫的问题。第一、 PARP抑制剂是高级别浆液性卵巢癌（HGSC）治疗的新的基本特征，但 许多患者最终在使用这些药物时发生癌症进展。因此，在项目1中，我们 设计的药物组合临床试验和相关研究，使我们能够系统地 扩大PARP抑制剂的使用。第二，我们认识到免疫疗法对实体瘤的新影响。 肿瘤治疗因此，在项目2中，我们为卵巢癌患者设计了一种新的疫苗试验。第三、 患有原发性难治性疾病的HGSC患者或癌症复发的患者 潜在的RAS突变，如低级别浆液性或粘液性癌症， 问题.因此，在项目3中，我们将探索新的非铂类药物组合，如 BCL抑制剂和MEK抑制剂的组合，并将检查预测性生物标志物和肿瘤 在细胞外活动中明显的反应。这个DF/HCC卵巢癌孢子的具体目的是， 目的1（项目1）：ATR受体介导的高级别浆液性结肠癌PARP抑制剂耐药性逆转 卵巢癌（HGSOC）;目标2（项目2）：联合个人新抗原靶向癌症疫苗与 卵巢癌的免疫检查点阻断;目标3（项目3）：曲美替尼+ 复发性卵巢癌的Navitoclax。

Project Summary (Overall) The Overall section of this Ovarian Cancer SPORE application describes the Background, Specific Aims, Innovation, and Research Plan of the three projects and four cores. We emphasize intra- SPORE collaborations and development of clinical trials with companion biomarkers. Through this SPORE application, we have tried to address several of the most urgent questions in ovarian cancer therapy. First, PARP inhibitors are a new and essential feature of high grade serous ovarian cancer (HGSC) therapy, but many patients eventually have cancer progression on these agents. Accordingly, in Project 1, we have designed clinical trials with drug combinations and correlative studies which will allow us to systematically extend the use of PARP inhibitors. Second, we recognize the emerging impact of immunotherapy on solid tumor treatment. Thus, in Project 2, we have designed a novel vaccine trial for ovarian cancer patients. Third, HGSC patients with primary refractory disease or those patients with recurrence whose cancer harbor underlying RAS mutations such as low grade serous or mucinous cancers pose a particularly difficult clinical problem. Accordingly, in Project 3, we will explore novel non-platinum drug combinations, such as the combination of a BCL inhibitor and a MEK inhibitor, and will examine predictive biomarkers and tumor responses evident in the extracellular activity. The Specific Aims of this DF/HCC ovarian cancer SPORE are as follows: Aim 1 (Project 1): ATR inhibitor-mediated reversal of PARP inhibitor resistance in high-grade serous ovarian cancer (HGSOC); Aim 2 (Project 2): Combined personal neoantigen-targeting cancer vaccines with immune checkpoint blockade for ovarian cancer; Aim 3 (Project 3): Evaluation of the Efficacy of Trametinib + Navitoclax in recurrent ovarian carcinoma.