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<30%。引入 聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPis）可增加患者的无进展生存期 并可能增加一些患者的总生存期;然而，PARPi耐药疾病的出现是一个潜在的风险。 不断升级的临床问题因此，迫切需要鉴定增强PARPi的新疗法。 HGSOC的活动。在这里，我们表明，塞瑞替尼，一种小分子激酶抑制剂批准用于治疗 ALK阳性非小细胞肺癌，与PARPis协同作用。这种协同作用不是由于ceritinib诱导的 同源重组（HR）破坏或ALK抑制。相反，塞瑞替尼与PARPis协同作用， 至少部分是通过抑制线粒体呼吸，这会诱导活性氧的产生 (ROS)随后诱导DNA损伤，通过PARP依赖性碱基切除报告修复 (BER)通路与这种作用机制一致，我们表明塞瑞替尼+ PARPi组合是 在HR-熟练的和-缺陷的卵巢癌细胞系中具有协同作用。此外，在HGSOC患者来源的 在异种移植（PDX）模型中，塞瑞替尼+奥拉帕尼（C+O）诱导肿瘤消退并延长小鼠生存期， 比单独使用奥拉帕尼更有效。这些观察提高了C+O将扩展无进展的可能性 存活或防止HGSOC中PARPi抗性的出现。尽管取得了这些进展， i）C + O是否可以安全地给予患者， iii）如何识别对C+O最有反应的卵巢癌。开始重新利用 塞瑞替尼治疗卵巢癌，我们建议i）进行一项C+O的Ib期试验，包括一个扩展队列， 铂敏感性复发性卵巢癌的相关研究; ii）鉴定基因和途径，包括DNA 修复途径，影响C+O细胞毒性，以提供更多的了解这一行动 iii）使用PDX模型来评估潜在的生物标志物; 与对C+O的抗肿瘤反应相关的基因型和表型差异。的总目标 这些研究是为了更好地理解C+O组合的作用机制，并确定卵巢 在未来的HGSOC II期试验中，最有可能对这种组合产生反应的癌症。这些研究， 利用生物标本、生物统计学和生物信息学以及动物模型核心，旨在促进 将塞瑞替尼与PARPi联合使用作为改善PARPi结局的新疗法- 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.