Project 3: Repurposing Ceritinib for Ovarian Cancer Therapy

项目 3：重新利用色瑞替尼治疗卵巢癌

• 批准号: 10452721
• 负责人: LARRY M KARNITZ
• 金额: $ 23.66万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2026-08-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452721
• 关键词: 3-Dimensional; Address; Affect; Animal Model; Antitumor Response; BRCA mutations; Base Excision Repairs; Bioinformatics; Biological Assay; Biological Markers; Biometry; CRISPR screen; Cancer Patient; Cancer cell line; Cell Line; Clinic; Clinical; Code; Cohort Studies; Correlative Study; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; Data; Defect; Development; Disease; Disease Resistance; Dose; Drug Kinetics; Excision; FDA approved; Future; Gene Mutation; Genes; Genotype; Goals; Immune system; Immunocompetent; In Vitro; Individual; Libraries; Maintenance Therapy; Malignant neoplasm of ovary; Mitochondria; Modeling; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oxidative Phosphorylation; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phase; Phase Ib Clinical Trial; Phase Ib Trial; Phenotype; Phosphotransferases; Plasma; Platinum; Poly(ADP-ribose) Polymerases; Process; Production; Progression-Free Survivals; Protein Tyrosine Kinase; Proteins; Reactive Oxygen Species; Recurrence; Relapse; Reporting; Resistance; Respiration; Safety; Sampling; Serous; Therapeutic; Time; Toxic effect; Woman; XRCC1 gene; base; brca gene; cancer cell; cancer therapy; cohort; cytotoxic; cytotoxicity; design; homologous recombination; improved outcome; in vivo; in vivo Model; inhibitor; insight; kinase inhibitor; loss of function; novel; novel therapeutics; partial response; patient derived xenograft model; patient registry; phase II trial; potential biomarker; preclinical study; predicting response; prevent; repaired; response; response biomarker; small molecule; synergism; tissue culture; tumor

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.

摘要 – 项目 3 晚期高级别浆液性卵巢癌 (HGSOC) 的 5 年生存率 <30%。介绍 聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPis）可延长患者的无进展生存期 并可能提高某些患者的总生存率；然而，PARPi 抗性疾病的出现是一个 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 中的活动。在这里，我们展示了色瑞替尼（ceritinib），一种被批准用于治疗的小分子激酶抑制剂 ALK 阳性非小细胞肺癌与 PARPis 具有协同作用。这种协同作用不是由于色瑞替尼引起的 同源重组 (HR) 破坏或 ALK 抑制。相反，色瑞替尼与 PARPis 具有协同作用， 至少部分是通过抑制线粒体呼吸来诱导活性氧的产生 (ROS) 以及随后诱导的 DNA 损伤，通过 PARP 依赖性碱基切除报告进行修复 （BER）路径。与这种作用机制一致，我们表明色瑞替尼 + PARPi 组合是 在 HR 丰富和缺乏的卵巢癌细胞系中具有协同作用。此外，在 HGSOC 中，源自患者的 异种移植 (PDX) 模型，色瑞替尼 + 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。这些观察结果提出了 C+O 将延长无进展期的可能性 生存或防止 HGSOC 中 PARPi 耐药性的出现。尽管取得了这些进展，但仍不清楚 i) C+O 是否可以安全地给予患者，ii) C+O 是否具有对抗患者 HGSOC 的活性，以及 iii) 如何识别对 C+O 最敏感的卵巢癌。开始重新调整用途的过程 色瑞替尼用于卵巢癌，我们建议 i) 通过扩展队列进行 C+O 的 Ib 期试验，并且 铂敏感复发性卵巢癌的相关研究； ii) 识别基因和途径，包括 DNA 修复途径，影响 C+O 细胞毒性，以便提供对该作用的更多见解 组合并潜在地识别反应的生物标志物； iii) 使用 PDX 模型评估潜力 与 C+O 抗肿瘤反应相关的基因型和表型差异。的总体目标 这些研究是为了更好地了解 C+O 组合的作用机制并确定卵巢 在 HGSOC 未来的 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，其中 利用生物样本、生物统计学和生物信息学以及动物模型核心，旨在促进 重新利用色瑞替尼与 PARPis 联合作为一种新疗法，以改善 PARPi 的结果 治疗 HGSOC。