Project 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian Cancer

项目2：治疗卵巢癌的下一代TOP1抑制剂

• 批准号: 10268764
• 负责人: SCOTT H KAUFMANN
• 金额: $ 26.21万
• 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/10268764
• 关键词: ABCG2 gene; Affect; Animal Model; Antibodies; BRCA mutations; BRCA1 gene; BRCA2 gene; Biochemical; Bioinformatics; Biological Markers; Biometry; Biopsy; CRISPR screen; Cancer Model; Cancer Patient; Cell Line; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Complex; DNA Damage; DNA Repair Enzymes; Development; Diagnostic Reagent; Disease; Disease Resistance; Epithelial ovarian cancer; Excision; Exhibits; FDA approved; Failure; Formulation; Gene Expression; Generations; Genes; Genetic; Genomics; Germ-Line Mutation; In Vitro; Infusion procedures; Investigation; Laboratories; Lead; Maintenance Therapy; Malignant neoplasm of ovary; Mammalian Oviducts; Marrow; Modeling; Mutation; NKTR gene; Neoplasm Circulating Cells; Neoplasms; Ovarian; PARP inhibition; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Platinum; Poly(ADP-ribose) Polymerases; Polyethylene Glycols; Pre-Clinical Model; Process; Prodrugs; Progression-Free Survivals; Recurrence; Refractory; Regimen; Relapse; Reporting; Resistance; SN-38; Schedule; Serous; Site; Somatic Mutation; Testing; Therapeutic; Topoisomerase I inhibition; Topoisomerase-I Inhibitor; Topotecan; Toxic effect; Type I DNA Topoisomerases; Woman; antibody detection; antitumor effect; bevacizumab; cell free DNA; cell killing; chemosensitizing agent; clinical practice; cohort; cytotoxicity; design; drug action; homologous recombination; improved; in vivo; inhibitor/antagonist; insight; irinotecan; nanoparticle; neoplastic cell; next generation; novel therapeutics; overexpression; patient derived xenograft model; peritoneal cancer; phase II trial; pre-clinical; preclinical study; protein expression; recombinational repair; resistance mechanism; response; sample archive; treatment response; tumor

ABSTRACT – PROJECT 2 Inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) are highly active in homol- ogous recombination (HR)-deficient ovarian cancers, especially those with BRCA1 or BRCA2 (BRCA1/2) muta- tions. Even in this setting, however, 40-80% of cases become PARP inhibitor (PARPi) resistant, most often as a result of genetic or biochemical changes that restore HR. Among other genomic subsets of ovarian cancer, PARPi resistance is even more prevalent. The observation that most common mechanisms of acquired PARPi resistance do not result from a failure to inhibit PARP1 raises the possibility that PARPis can potentially be utilized as chemosensitizing agents in this setting if suitable combinations can be identified. Accordingly, the present project seeks to enhance the efficacy of the PARPi rucaparib and extend its use by combining it with a 3rd generation topoisomerase I (TOP1) inhibitor (TOP1i). Recent studies have shown that nanoparticle formulations such as PLX038, a polyethylene glycol-conjugated ultra-long acting form of the TOP1i 7-ethyl-10- hydroxycamptothecin (SN-38), exhibit less marrow toxicity and greater efficacy than conventional TOP1is in preclinical cancer models. Our preliminary studies show that sustained release TOP1is, including PLX038, are active against five of seven PARPi-resistant ovarian cancer patient-derived xenografts (PDXs) tested. Moreover, using a unique antibody that detects TOP1-DNA covalent complexes (TOP1ccs), which are intermediates in the TOP1i-induced killing process, we have shown that TOP1ccs are diminished or undetectable in PDXs that are resistant to the TOP1i/PARPi combination, providing a starting point for understanding ovarian cancer resistance to this treatment. Collectively, these results lead to the hypothesis that a readily identifiable subset of HR- proficient ovarian cancers will exhibit sustained antitumor effects when treated with a next generation TOP1i alone or in combination with a PARPi. To test this hypothesis, we now propose to i) assess the efficacy of PLX038, alone and in combination with the PARPi rucaparib, in a cohort of genomically profiled high grade serous ovarian cancer PDXs with intrinsic or acquired resistance to single agent PARPis to identify the spectrum of ovarian cancers that could potentially benefit from PLX038 or the combination; ii) identify mechanisms of resistance to the TOP1i/PARPi combination in PDXs and cell lines; and iii) examine the association between the formation of drug-stabilized TOP1-DNA covalent complexes in tumor cells and the response of ovarian cancer patients to the PLX038/rucaparib combination in a phase II clinical trial. Collectively, these studies will not only provide insight into the genomic and biochemical factors that affect response to a 3rd generation TOP1i in ovarian cancer, but also determine whether it is possible to use PARPis as chemosensitizing agents in settings where they are no longer active as single agents. If successful, this project will point to a new therapy for the growing number of women with PARPi-resistant ovarian cancer.

摘要 - 项目2 DNA修复酶聚（ADP-核糖）聚合酶1（PARP1）的抑制剂高度活跃 怪异重组（HR）缺乏卵巢癌，尤其是患有BRCA1或BRCA2（BRCA1/2）muta-的卵巢癌 tions。但是，即使在这种情况下，40-80％的病例也成为PARP抑制剂（PARPI），最常见的是 恢复人力资源的遗传或生化变化的结果。除其他卵巢癌基因组子集外， PARPI抗性更为普遍。观察到获得的parpi的最常见机制 抗性不是由于未能抑制PARP1而导致的，这可能会增加parpis的可能性。 如果可以鉴定合适的组合，则在这种情况下用作化学敏化剂。根据， 目前的项目旨在提高parpi rucaparib的效率，并通过将其与 第三代拓扑异构酶I（TOP1）抑制剂（TOP1I）。最近的研究表明纳米颗粒 公式，例如PLX038，TOP1I 7-乙基-10-- 与常规TOP1I相比 临床前癌模型。我们的初步研究表明，包括PLX038在内的持续释放top1is是 在测试的七个耐parpi卵巢癌患者衍生的Xenographictics（PDXS）中，有五个测试。而且， 使用检测TOP1-DNA共价复合物（TOP1CC）的独特抗体，该复合物是中间体 TOP1I引起的杀戮过程，我们已经证明TOP1CC在PDX中降低或无法检测到 对TOP1I/PARPI组合有抗性，为了解卵巢癌的起点提供了一个起点 对此治疗。总的来说，这些结果导致了以下假设： 熟练性卵巢癌在接受下一代治疗时会持续抗肿瘤作用 单独或与Parpi结合使用TOP1I。为了检验这一假设，我们现在建议i）评估效率 PLX038，单独并与parpi rucaparib结合在一起 具有内在或获得对单药parpis抗性的浆液卵巢癌PDXs以识别光谱 可能从PLX038或组合中受益的卵巢癌； ii）确定机制 PDX和细胞系中TOP1I/PARPI组合的抗性； iii）检查 肿瘤细胞中药物稳定的TOP1-DNA共价复合物和卵巢癌的反应 在II期临床试验中，PLX038/rucaparib组合的患者。总的来说，这些研究不仅将 提供有关影响卵巢第三代TOP1I反应的基因组和生化因素的见解 癌症，但还确定是否可以在某些情况下使用Parpis作为化学敏化剂 它们不再是单个代理。如果成功，该项目将指出一种新的疗法 抗parpi卵巢癌的女性人数。