Project 3: Repurposing Ceritinib for Ovarian Cancer Therapy

摘要--项目3 晚期高级别浆液性卵巢癌(HGSOC)的5年生存率为30%。介绍了 多聚(ADP-核糖)聚合酶(PARP)抑制剂(PARPis)可增加患者的无进展生存率 并可能增加一些患者的总体存活率；然而，耐PARPI疾病的出现是一种 不断升级的临床问题。因此，迫切需要确定增强PARPI的新疗法 HGSOC的活动。在这里，我们展示了Ceritinib，一种被批准用于治疗糖尿病的小分子激酶抑制剂。 ALK阳性的非小细胞肺癌，与PARPis有协同作用。这种协同作用不是由于西里替尼诱导的 破坏同源重组(HR)或ALK抑制。相反，Ceritinib与PARPis有协同作用，在 至少在一定程度上，是通过抑制线粒体呼吸，从而诱导产生活性氧物种 (ROS)和随后通过PARP依赖的碱基切除报告修复的DNA损伤的诱导 (BER)途径。与这种作用机制一致，我们证明了Ceritinib+PARPI的组合是 在HR熟练和缺乏HR的卵巢癌细胞系中的协同作用。此外，在HGSOC患者中 异种移植(PDX)模型，Ceritinib+olaparib(C+O)诱导肿瘤消退并进一步延长小鼠存活时间 比单独使用奥拉帕里布更有效。这些观察结果增加了C+O扩展无进展的可能性 存活或阻止HGSOC中PARPI耐药的出现。尽管取得了这些进展，但仍不清楚 一)C+O能否安全地给患者服用，二)C+O在患者体内是否具有抗HGSOC活性，以及 三)如何确定对C+O最敏感的卵巢癌。开始重新调整用途的过程 Ceritinib治疗卵巢癌，我们建议：i)在扩大队列中进行C+O的Ib期试验， 铂敏感复发性卵巢癌的相关研究；ii)确定基因和途径，包括DNA 修复影响C+O细胞毒性的通路，以提供对这一作用的更多了解 组合并潜在地识别响应的生物标志物；以及iii)使用PDX模型来评估潜力 与C+O抗肿瘤反应相关的基因和表型差异 这些研究是为了更好地了解C+O组合的作用机制(S)，并识别卵巢 在未来的HGSOC第二阶段试验中，癌症最有可能对这种组合产生反应。这些研究，其中 利用生物谱系、生物统计学和生物信息学以及动物模型核心，旨在促进 塞利替尼联合PARP的再利用是改善PARPI预后的新方法。 治疗HGSOC。

ABSTRACT – PROJECT 3 The 5-year survival for advanced high-grade serous ovarian cancer (HGSOC) is <30%. The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) has increased progression-free survival in patients and may increase overall survival in some patients; however, the emergence of PARPi-resistant disease is an escalating clinical problem. Accordingly, there is a pressing need to identify novel therapies that enhance PARPi activity in HGSOC. Here we show that ceritinib, a small molecule kinase inhibitor approved for the treatment of ALK-positive non-small cell lung cancer, synergizes with PARPis. This synergy is not due to ceritinib-induced disruption of homologous recombination (HR) or ALK inhibition. Instead, ceritinib synergizes with PARPis, at least in part, by inhibiting mitochondrial respiration, which induces the production of reactive oxygen species (ROS) and consequent induction of DNA damage that is repaired via the PARP-dependent base excision report (BER) pathway. Consistent with this mechanism of action, we show that a ceritinib + PARPi combination is synergistic in HR-proficient and -deficient ovarian cancer cell lines. Moreover, in HGSOC patient-derived xenograft (PDX) models, ceritinib + olaparib (C+O) induces tumor regressions and extends mouse survival more effectively than olaparib alone. These observations raise the possibility that C+O will extend progression-free survival or prevent the emergence of PARPi resistance in HGSOC. Despite this progress, it remains unclear i) whether C+O can be safely given to patients, ii) whether C+O has activity against HGSOC in patients, and iii) how to identify the ovarian cancers that will be most responsive to C+O. To begin the process of repurposing ceritinib for ovarian cancer, we propose to i) perform a phase Ib trial of C+O with an expansion cohort and correlative studies in platinum-sensitive relapsed ovarian cancer; ii) identify genes and pathways, including DNA repair pathways, that affect C+O cytotoxicity in order to provide additional insight into the action of this combination and potentially identify biomarkers of response; and iii) use PDX models to assess potential genotypic and phenotypic differences that correlate with antitumor responses to C+O. The overarching goals of these studies are to better understand the mechanism(s) of action of the C+O combination and identify ovarian cancers most likely to respond to this combination in a future phase II trial in HGSOC. These studies, which utilize the Biospecimens, Biostatistics and Bioinformatics, and Animal Models Cores, are designed to facilitate the repurposing of ceritinib in combination with PARPis as a new therapy to improve the outcomes of PARPi- treated HGSOC.