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: 10606619
• 负责人: Qien Wang
• 金额: $ 33.96万
• 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/10606619
• 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) Polymerase Inhibitor; 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; 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; synergism; 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.

总结 聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）是一种令人兴奋和有前途的新一类药物， 抗癌药物，已被FDA批准用于BRCA 1或BRCA 2复发性卵巢癌 作为铂敏感性卵巢癌一线治疗后的维持治疗， BRCA基因突变PARPi通过合成致死性选择性杀死BRCA 1/2缺陷癌细胞。然而，在这方面， 接受PARPi治疗的患者最终发生癌症进展，并获得PARP抑制剂耐药性 仍然是一个临床障碍。获得性PARPi抗性的潜在机制之一是恢复 DNA修复能力，主要通过BRCA 1/2的二次突变。我们的初步研究 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ALDH家族的同种型ALDH 1A 1的表达。此外，我们还发现， ALDH 1A 1能够增强微同源介导的末端连接（MMEJ），这是修复的途径之一 DNA双链断裂（DSB）增强了DNA聚合酶θ（Pol θ）的表达，Pol θ是DNA聚合酶的关键参与者。 MMEJ通路，以及降低BRCA 2突变的卵巢癌细胞对PARPi的敏感性。基于 在这个科学前提下，我们提出了一个假设，PARPi诱导的ALDH 1A 1过表达增强了 MMEJ通过增加Pol θ的表达，并促进HR缺陷的PARPi治疗后的细胞存活。 癌细胞，最终导致获得性PARPi抗性。因此，ALDH 1A 1的抑制应该是有效的。 能够与PARPi协同治疗HR缺乏型EOC，并逆转HR缺乏型EOC患者对PARPi的耐药性。 平等机会委员会该提案的主要目标是确定有助于PARPi的新机制。 BRCA 1/2突变的EOC细胞中的耐药性，并测试靶向这种机制在预防和 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 我们的目标在具体目标1中，我们将确定PARPi诱导的MMEJ增强的潜在机制。 在HR缺陷型EOC细胞中的作用及其对PARPi抗性的贡献。在具体目标2中，我们将确定 ALDH 1A 1抑制剂NCT-505在预防和逆转PARPi耐药性方面的治疗潜力 BRCA 1/2突变的EOC在体外和体内。我们希望在这个项目结束时，我们将 已经证明了一种新的机制，有助于在HR缺乏的EOC中产生PARPi抗性。 我们还将展示ALDH 1A 1抑制剂在治疗这些患者中的治疗潜力。