NAD+ metabolism in PARP inhibitor resistance of ovarian cancer

NAD 代谢在卵巢癌 PARP 抑制剂耐药中的作用

• 批准号: 10612910
• 负责人: Arun Kanakkanthara
• 金额: $ 21.03万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612910
• 关键词: Anabolism; BRCA1 gene; BRCA2 gene; Binding; Cancer Relapse; Cancer cell line; Cells; Clinical; Clinical Trials; Collaborations; DNA Repair; Data; Deacetylase; Deacetylation; Defect; Dependence; Development; Disease; Disease Resistance; Excision; Gene Expression; Genes; Genetic Transcription; Goals; Hypersensitivity; In Vitro; In complete remission; Maintenance Therapy; Malignant Female Reproductive System Neoplasm; Malignant neoplasm of ovary; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Mutate; Mutation; Nicotinamide-Nucleotide Adenylyltransferase; Pathway interactions; Patients; Phase I Clinical Trials; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Poly(ADP-ribose) Polymerases; Pre-Clinical Model; Proteins; Publishing; Recurrent disease; Regulator Genes; Relapse; Research; Resistance; Resistance development; Role; SIRT1 gene; Serine; Serous; Testing; Therapeutic; Translating; Up-Regulation; Work; brca gene; cancer cell; design; effective therapy; efficacy testing; homologous recombination; in vivo; inhibitor; insight; mouse model; mutant; novel; novel therapeutics; overexpression; patient derived xenograft model; promoter; resistance mechanism; restoration; standard care; synergism; tumor

PROJECT SUMMARY/ABSTRACT High-grade serous ovarian cancer (HGSOC) remains the deadliest form of ovarian cancer, in part because most patients develop recurrent disease that is resistant to standard treatment, including platinum. Poly(ADP- ribose) polymerase (PARP) inhibitors (PARPis) have recently been approved as an important therapy for HGSOCs, especially for HGSOCs with defects in homologous recombination (HR) DNA repair due to mutations in BRCA1 or BRCA2. However, over 70% HGSOCs that initially respond to PARPis later develop resistant disease. Unfortunately, the underlying mechanisms of PARPi resistance are poorly understood. This project is designed to understand acquired PARPi resistance mechanisms and associated therapeutic vulnerabilities in HR-defective HGSOC. Our preliminary studies using HR-deficient HGSOC cell lines and patient derived xenograft (PDX) models show that acquired PARPi resistance is associated with high levels of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1). Our results also show that NMNAT1 upregulation results in an increase in NAD+ levels, which restores HR and creates a unique metabolic dependency in PARPi-resistant cells. These findings led to our central hypothesis that HR-deficient HGSOC acquire PARPi resistance by upregulating NMNAT1 that induces NAD+ levels leading to HR restoration as well as causing a metabolic dependency that may be therapeutically tractable. Guided by strong preliminary data, we propose three specific aims to: 1) examine how NMNAT1 is upregulated in HGSOC cells; 2) determine how NMNAT1 induces PARPi resistance; and 3) test whether NMNAT1-induced metabolic dependency in PARPi- resistant tumors can be targeted in preclinical models of HGSOC. These studies will unveil a previously unknown mechanism by which HGSOC cells become resistant to PARPis and may identify a potential new therapeutic option for PARPi-resistant HGSOC. The proposed work comprises an essential step toward our long-term goal of developing effective therapy for patients with HGSOC.

项目总结/摘要 高级别浆液性卵巢癌（HGSOC）仍然是卵巢癌中最致命的形式，部分原因是 大多数患者发展为对标准治疗（包括铂）有抗性的复发性疾病。聚ADP- 核糖）聚合酶（PARP）抑制剂（PARPis）最近已被批准作为一种重要的治疗 HGSOC，特别是对于同源重组（HR）DNA修复缺陷的HGSOC，由于 BRCA 1或BRCA 2突变。然而，超过70%的HGSOC最初对PARP有反应， 抵抗疾病。不幸的是，PARPi抗性的潜在机制知之甚少。这 该项目旨在了解获得性PARPi耐药机制和相关的治疗方法。 人力资源缺陷HGSOC的漏洞。我们的初步研究使用HR缺陷的HGSOC细胞系， 患者来源的异种移植物（PDX）模型显示获得性PARPi抗性与高水平的 烟酰胺单核苷酸腺苷酰转移酶1（NMNAT 1）。我们的研究结果还表明，NMNAT 1 上调导致NAD+水平增加，从而恢复HR并产生独特的代谢产物。 PARPi抗性细胞中的依赖性。这些发现导致了我们的中心假设，即HR缺陷的HGSOC 通过上调NMNAT 1获得PARPi抗性，NMNAT 1诱导NAD+水平，导致HR恢复 导致代谢依赖，这可能是治疗上容易处理的。在强有力的初步数据的指导下， 我们提出了三个具体的目标：1）检查NMNAT 1在HGSOC细胞中是如何上调的; 2）确定NMNAT 1在HGSOC细胞中是如何上调的。 NMNAT 1诱导PARPi抗性;和3）测试NMNAT 1是否诱导PARPi-1中的代谢依赖性。 在HGSOC的临床前模型中可以靶向耐药肿瘤。这些研究将揭示一个以前 HGSOC细胞对PARPis产生抗性的未知机制，并可能发现一种潜在的新的 PARPi耐药HGSOC的治疗选择。拟议中的工作是我们朝着 长期目标是为HGSOC患者开发有效治疗。