AML mutation-guided drugging of DNA repair

AML突变引导的DNA修复药物

• 批准号: 9885053
• 负责人: ALEXANDER V MAZIN
• 金额: $ 59.55万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9885053
• 关键词: Acute Myelocytic Leukemia; Affect; BRCA1 gene; BRCA2 gene; Back; Base Excision Repairs; Cells; Chromosome abnormality; Cytotoxic agent; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA lesion; DNA replication fork; Data; Defect; Dominant-Negative Mutation; Double Effect; Double Strand Break Repair; Down-Regulation; Drug Targeting; Gene Expression; Gene Expression Profiling; Gene Mutation; Generations; Genes; Genetic; Genotoxic Stress; Goals; In Vitro; Individual; Induced Mutation; Knock-out; Knowledge; Lead; Malignant Neoplasms; Mediating; Modality; Mutate; Mutation; Mutation Analysis; Nonhomologous DNA End Joining; Normal Cell; Normal tissue morphology; Oxidative Stress; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Proliferating; Proteins; RAD51C gene; RAD52 gene; Reactive Oxygen Species; Regimen; Reporting; Role; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Effect; XRCC2 gene; XRCC3 gene; acute myeloid leukemia cell; base; burden of illness; cancer cell; comparative efficacy; design; drug standard; genotoxicity; homologous recombination; improved; in vivo; individual patient; inhibitor/antagonist; leukemia; leukemic stem cell; novel; novel therapeutic intervention; paralogous gene; personalized medicine; preference; prevent; recombinational repair; repaired; standard care; stem cells; therapeutic evaluation; treatment response

Current treatments of acute myeloid leukemia (AML) clear the disease burden consisting mostly of leukemia progenitor cells (LPCs), but they usually fail to eradicate leukemia stem cells (LSCs). Altered DNA repair mechanisms may be responsible for survival of LSCs and/or LPCs under genotoxic stress. DNA double-strand breaks (DSBs), the most lethal DNA lesions, are usually repaired by BRCA -mediated homologous recombination (HR) repair at the replication forks. BRCA-HR repair involves several proteins such as BRCA1, BRCA2, RAD54 and RAD51. An alternative HR pathway depends on RAD52-RAD51 (RAD52-HR). PARP1-mediated base excision repair (BER) and PARP1-dependent non-homologous end-joining (P-NHEJ) serve as back-ups/alternative mechanisms to prevent and/or repair DSBs. Cancer-specific defects in DNA repair create the opportunity to employ a phenomenon called synthetic lethality, e.g. elimination of BRCA1/2-mutated cancer cells by PARP1 inhibitor (PARP1i). Since inactivating mutations in BRCA-HR pathway are rare in AMLs, we obtained preliminary data suggesting that BRCA deficiency and BRCA proficiency on individual AMLs can be predicted by a comprehensive Gene Mutation Analysis (GMA) of AML-inducing genetic aberrations. This approach will be tested in Aim #1. BRCA-deficient AML LSCs/LPCs should be prone to PARP1i-induced synthetic lethality. However, therapeutic effect of PARP1i in BRCA1/2-deficient cells may be reduced by alternative RAD52-HR, which can protect, at least partially, BRCA-deficient PARP1i-treated cells from lethal effect of DSBs. Therefore, in Aim #2 we propose that combination of PARP1i+RAD52i may induce more effective synthetic lethality in BRCA deficient LSCs/LPCs. We will also develop drug-grade RAD52i. On the other hand, BRCA-proficient AML cells should be sensitive to the inhibitors of BRCA- HR pathway combined with PARP1i. Preliminary data suggest that RAD54 may be a valid target to induce BRCA-deficiency in BRCA-proficient cells. In Aim #3 we will examine if targeting RAD54 sensitizes BRCA-proficient AMLs to PARP1i - mediated synthetic lethality. We expect that personalized medicine-guided synthetic lethality combining drugs targeting DNA repair may be designed to eliminate AML LSCs/LPCs in individual patients.

目前急性髓系白血病 (AML) 的治疗方法消除了疾病负担，主要包括 白血病祖细胞（LPC），但它们通常无法根除白血病干细胞 （LSC）。 DNA 修复机制的改变可能是 LSC 和/或 LPC 存活的原因 在遗传毒性应激下。 DNA 双链断裂 (DSB) 是最致命的 DNA 损伤 通常通过复制时 BRCA 介导的同源重组 (HR) 修复来修复 叉子。 BRCA-HR 修复涉及多种蛋白质，例如 BRCA1、BRCA2、RAD54 和 RAD51。 另一种 HR 途径依赖于 RAD52-RAD51 (RAD52-HR)。 PARP1介导的碱基 切除修复 (BER) 和 PARP1 依赖性非同源末端连接 (P-NHEJ) 充当 防止和/或修复 DSB 的备份/替代机制。 DNA 修复中的癌症特异性缺陷创造了利用现象的机会 称为综合致死率，例如PARP1抑制剂消除BRCA1/2突变的癌细胞 （PARP1i）。由于 BRCA-HR 通路失活突变在 AML 中很少见，我们获得 初步数据表明 BRCA 缺乏和 BRCA 熟练对个体 AML 的影响 可以通过对 AML 诱发基因进行全面的基因突变分析 (GMA) 进行预测 像差。该方法将在目标#1 中进行测试。 BRCA 缺陷的 AML LSC/LPC 应该容易发生 PARP1i 诱导的合成致死。 然而，PARP1i 在 BRCA1/2 缺陷细胞中的治疗效果可能会因以下因素而降低： 替代 RAD52-HR，可以​​至少部分保护经过 BRCA 缺陷的 PARP1i 治疗 细胞免受 DSB 的致死作用。因此，在目标 2 中，我们建议将 PARP1i+RAD52i 可能在 BRCA 缺陷的 LSC/LPC 中诱导更有效的合成致死作用。 我们还将开发药物级RAD52i。 另一方面，BRCA 熟练的 AML 细胞应该对 BRCA-抑制剂敏感。 HR 通路与 PARP1i 结合。初步数据表明 RAD54 可能是一个有效的目标 在 BRCA 熟练细胞中诱导 BRCA 缺陷。在目标 #3 中，我们将检查是否瞄准 RAD54 使 BRCA 熟练的 AML 对 PARP1i 介导的合成致死敏感。 我们期望个性化药物引导的合成杀伤力结合药物靶向 DNA 修复可能旨在消除个体患者的 AML LSC/LPC。