Role of ALDH in PARP inhibitor resistance in HR-deficient ovarian cancer

ALDH 在 HR 缺陷卵巢癌 PARP 抑制剂耐药中的作用

• 批准号: 10394792
• 负责人: Qien Wang
• 金额: $ 34.02万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394792
• 关键词: Aldehydes; Antineoplastic Agents; BRCA mutations; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Binding; Cell Death; Cell Survival; Cells; Chemoresistance; Clinical; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA replication fork; DNA-Directed DNA Polymerase; Development; Double Strand Break Repair; Enzymes; Epithelial ovarian cancer; FDA approved; Family; Female; Genes; Genetic Transcription; Goals; In Vitro; Maintenance Therapy; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Metabolism; Mutate; Nonhomologous DNA End Joining; Pathway interactions; Patients; Platinum; Poly(ADP-ribose) Polymerases; Polymerase; Production; Promoter Regions; Protein Isoforms; Recurrence; Relapse; Reporting; Resistance; Resistance development; Retina; Retinoic Acid Receptor; Retinoic Acid Response Element; Role; Survival Rate; Testing; Therapeutic; Tretinoin; aldehyde dehydrogenases; base; brca gene; cancer cell; efficacy testing; expectation; homologous recombination; improved; in vivo; inhibitor; mouse model; mutant; mutation carrier; novel; overexpression; patient derived xenograft model; prevent; recombinational repair; repaired; reproductive tract; restoration; targeted treatment; therapeutic evaluation; tumor progression

Summary Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are an exciting and promising new class of anticancer drugs, which have been approved by the FDA for recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy after frontline therapy for platinum sensitive ovarian cancer regardless of BRCA mutation. PARPi selectively kill BRCA1/2-deficient cancer cells through synthetic lethality. However, patients receiving PARPi eventually develop cancer progression, and acquired PARP inhibitor resistance remains a clinical hurdle. One of the mechanisms underlying acquired PARPi resistance is the restoration of DNA repair capacity, mainly through the secondary mutations of BRCA1/2. Our preliminary study has demonstrated that PARPi can enhance the Aldehyde dehydrogenase (ALDH) activity in ovarian cancer cells, mainly through inducing expression of ALDH1A1, an isoform of the ALDH family. In addition, we also found that ALDH1A1 is able to augment the microhomology-mediated end joining (MMEJ), one of the pathways for repairing DNA double-strand breaks (DSBs), enhance the expression of DNA polymerase θ (Pol θ), a key player in the MMEJ pathway, as well as reduce the sensitivity of BRCA2 mutated ovarian cancer cells to PARPi. Based on this scientific premise, we generate a hypothesis that PARPi-induced overexpression of ALDH1A1 enhances MMEJ via increasing the expression of Pol θ, and promotes cell survival after PARPi treatment in HR-deficient cancer cells, eventually leading to acquired PARPi resistance. Consequently, inhibition of ALDH1A1 should be able to synergize with PARPi in treating HR-deficient EOC, and reverse resistance to PARPi in HR-deficient EOC. The main objective of this proposal is to determine a novel mechanism that contributes to PARPi resistance in BRCA1/2-mutated EOC cells, and test the efficacy of targeting this mechanism in preventing and reversing PARPi resistance in these cells. Two specific aims are proposed to test this hypothesis and achieve our goal. In specific aim 1, we will determine the mechanism underlying PARPi-induced augmentation of MMEJ in HR-deficient EOC cells and its contribution to PARPi resistance. In specific aim 2, we will determine the therapeutic potential of an ALDH1A1 inhibitor, NCT-505, in preventing and reversing PARPi resistance in BRCA1/2-mutated EOC in vitro and in vivo. It is our expectation that at the conclusion of this project, we will have demonstrated a new mechanism contributing to the development of PARPi resistance in HR-deficient EOC. We will have also shown the therapeutic potential of an ALDH1A1 inhibitor in treating these patients.

概括 聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPI）是令人兴奋且有希望的新类别 抗癌药物已获得FDA的批准用于复发性卵巢癌，brca1或brca2 突变，作为铂敏感卵巢癌的一线治疗后的维持疗法，无论如何 BRCA突变。 PARPI通过合成的致死性选择性地杀死BRCA1/2缺陷癌细胞。然而， 接受PARPI的患者最终发展出癌症的进展，并获得了PARP抑制剂耐药性 仍然是临床障碍。获得的PARPI抗性的基础机制之一是恢复 DNA修复能力，主要通过BRCA1/2的次要突变。我们的初步研究有 证明PARPI可以增强卵巢癌细胞中的醛脱氢酶（ALDH）活性， 主要通过诱导的ALDH1A1的表达，ALDH1A1是ALDH家族的同工型。此外，我们还发现 ALDH1A1能够增强微学介导的末端连接（MMEJ），这是修复的途径之一 DNA双链断裂（DSB），增强了DNA聚合酶θ（polθ）的表达，这是一个关键参与者 MMEJ途径以及降低BRCA2突变卵巢癌细胞对PARPI的敏感性。基于 这个科学的前提，我们产生了一个假设，即parpi诱导的Aldh1a1的过表达增强了 MMEJ通过增加polθ的表达，并在HR缺乏症中促进PARPI处理后的细胞存活 癌细胞，最终导致获得的PARPI耐药性。因此，抑制aldh1a1应该是 可以与PARPI协同治疗HR缺乏EOC，并在HR缺乏方面对PARPI进行反向抗性 EOC。该提案的主要目的是确定有助于PARPI的新型机制 BRCA1/2突变的EOC细胞的耐药性，并测试针对这种机制预防和 逆转这些细胞中的parpi抗性。提出了两个具体目标来检验这一假设并实现 我们的目标。在特定目标1中，我们将确定parpi诱导的MMEJ的增加的机制 在缺乏HR的EOC细胞及其对PARPI耐药性的贡献中。在特定目标2中，我们将确定 ALDH1A1抑制剂NCT-505的治疗潜力在预防和逆转PARPI抗性方面 BRCA1/2在体外和体内Mutated EOC。我们期望在这个项目结束时，我们将 已经证明了一种新的机制，该机制有助于HR缺陷EOC中PARPI耐药性的发展。 我们还将显示ALDH1A1抑制剂治疗这些患者的治疗潜力。