AML mutation-guided drugging of DNA repair

AML突变引导的DNA修复药物

• 批准号: 10543192
• 负责人: ALEXANDER V MAZIN
• 金额: $ 54.99万
• 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/10543192
• 关键词: Acute Myelocytic Leukemia; Affect; BRCA deficient; BRCA1 gene; BRCA2 gene; Base Excision Repairs; Cell Proliferation; 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 Combinations; Drug Targeting; Gene Expression; Gene Expression Profiling; Gene Mutation; Generations; Genes; Genetic; Genetic Induction; Genotoxic Stress; Goals; In Vitro; Individual; Induced Mutation; Knock-out; Knowledge; Malignant Neoplasms; Mediating; Modality; Mutate; Mutation; Mutation Analysis; Nonhomologous DNA End Joining; Normal Cell; Normal tissue morphology; Oxidative Stress; PALB2 gene; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Play; Poly(ADP-ribose) Polymerase Inhibitor; 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; brca gene; burden of illness; cancer cell; comparative efficacy; design; drug standard; drug-like compound; genotoxicity; homologous recombination; improved; in vivo; individual patient; inhibitor; leukemia; leukemic stem cell; novel; novel therapeutic intervention; paralogous gene; personalized medicine; preference; prevent; recombinational repair; repaired; standard care; stem; 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.

急性髓样白血病（AML）的当前治疗方法清除了疾病负担，主要是 白血病祖细胞（LPC），但通常无法消除白血病干细胞 （LSC）。 DNA修复机制的改变可能是LSC和/或LPC的存活率的原因 在遗传毒性应激下。 DNA双链断裂（DSB），最致命的DNA病变是 通常在复制时通过BRCA介导的同源重组（HR）修复修复 叉子。 BRCA-HR修复涉及多种蛋白质，例如BRCA1，BRCA2，RAD54和RAD51。 另一种HR途径取决于RAD52-RAD51（RAD52-HR）。 PARP1介导的碱 切除修复（BER）和PARP1依赖性非同源末端连接（P-NHEJ）作为 预防和/或修复DSB的备用/替代机制。 DNA修复中的癌症特异性缺陷创造了使用现象的机会 称为合成致死性，例如通过PARP1抑制剂消除BRCA1/2突变的癌细胞 （PARP1I）。由于BRCA-HR途径中的灭活突变在AML中很少见，因此我们获得了 初步数据表明BRCA缺乏症和BRCA对单个AML的水平 可以通过诱导AML遗传的综合基因突变分析（GMA）来预测 畸变。该方法将在AIM＃1中进行测试。 缺乏BRCA的AML LSC/LPC应该容易容易诱发的合成致死性。 但是，PARP1I在BRCA1/2缺陷细胞中的治疗作用可能会通过 替代RAD52-HR，至少可以部分保护BRCA缺陷PARP1I-TERATEC DSB致死作用的细胞。因此，在AIM＃2中，我们建议 PARP1I+RAD52I可能会在BRCA缺乏LSC/LPC中引起更有效的合成致死性。 我们还将开发药物级Rad52i。 另一方面，BRCA的AML细胞应对BRCA-的抑制剂敏感 人力资源途径与PARP1I结合。初步数据表明RAD54可能是有效的目标 诱导BRCA的富有BRCA细胞的缺陷。在AIM＃3中，我们将检查是否针对 RAD54将BRCA的AML敏感到PARP1I-介导的合成致死性。 我们希望个性化的药物引导的合成致死性将药物靶向靶向 DNA修复旨在消除个别患者的AML LSC/LPC。