Mechanisms of Parp inhibitor-induced bone marrow toxicities

项目总结 聚腺苷二磷酸核糖聚合酶(PARP)抑制剂作为一类药物被认为是非常成功的药物之一 精准医药与食品药品监督管理局药品审批不断积累的故事 不同癌症类型患者的比例。此外，临床前研究正在调查它们在 大量的非恶性疾病。这些药物同时抑制多种PARP酶，其中一些是 感知和协调修复几种类型的DNA损伤的关键酶。此外，这些药物还设置了陷阱 将PARP1酶结合到DNA上，导致DNA双链断裂来解决这个病变。因此，通过设计， 这些药物增加了细胞中的DNA损伤，引起了人们的担忧，即它们可能对正常细胞产生毒性，甚至发生突变 依赖PARP酶发挥功能的细胞。因此，临床试验和药物安全数据库显示严重 骨髓不良反应，包括严重的，有时是不可逆转的血细胞计数下降，以及 与治疗相关的致命性骨髓癌风险增加表明，造血干细胞和祖细胞 细胞对PARP抑制剂的作用是唯一敏感的。然而，机制和因果关系尚不清楚。 长期目标是了解正常的骨髓功能，以及如果有生殖系或 他们骨髓细胞中的获得性突变特别容易受到特定基因的不利影响 曝光。中心假设是1)PARP抑制剂，由于它们有能力延缓复制分叉和 导致双链DNA断裂，损害造血干细胞和祖细胞的增殖，导致 最增殖的亚群的血细胞产量比其他亚群减少得更多，2)这些PARP 抑制效应动员长期干细胞以帮助满足血液生产需求，同时 创造一个竞争的环境，在这种环境中，携带TP53或其他突变的干细胞有望在野外生长。 类型，但最终会使患者发生骨髓衰竭或白血病。这个项目的基本原理是 一组不断扩大的患者正在接受PARP抑制剂的治疗，许多人经历了严重的血液循环 和骨髓毒性，包括与治疗相关的血癌的发展，但其机制和 预防这些严重毒性的方法尚不清楚。利用小鼠和人类的体外和体内模型， 我们将通过以下具体目标来检验这些假说：1)确定PARP抑制剂如何破坏正常 造血导致细胞减少；2)确定PARP抑制剂是否创造了选择性环境 并揭示了不同基因型别的造血干细胞和祖细胞的适应性差异 让这些细胞自行变异。 这项申请中提出的研究是创新的，因为这是第一次确定 同时抑制多种PARP酶会在机制水平上影响正常的造血。这 该提案意义重大，因为它将允许确定安全使用PARP抑制剂的预防策略，并 通过PARP酶操作改善造血的新药物靶点。

PROJECT SUMMARY Poly-(ADP ribose) polymerase (PARP) inhibitors as a drug class are considered one of the great success stories of Precision Medicine with Food and Drug Administration drug approvals accumulating for growing proportions of patients with diverse cancer types. As well, preclinical studies are investigating their use in a multitude of non-malignant diseases. These drugs inhibit multiple PARP enzymes at once, some of which are critical enzymes for sensing and coordinating repair of several types of DNA damage. Further, these drugs trap the PARP1 enzyme onto DNA, resulting in a DNA double strand break to resolve this lesion. Thus, by design, these drugs increase DNA damage in cells, raising concern that they could be toxic to or even mutate normal cells that rely on PARP enzymes for their functions. Thus, clinical trial and drug safety databases showing serious bone marrow adverse effects, including severe, and sometimes irreversible lowering of the blood counts, and an increased risk of deadly therapy-related bone marrow cancers suggest that hematopoietic stem and progenitor cells are uniquely susceptible to PARP inhibitor effects. However, mechanism and causation are not yet clear. The long-term goal is to understand normal bone marrow function and if patients with germline or acquired mutations in their bone marrow cells are uniquely susceptible to the adverse effects of specific exposures. The central hypothesis is that 1) PARP inhibitors, due to their ability to stall replication forks and cause double strand DNA breaks, impair hematopoietic stem and progenitor cell proliferation, resulting in decreased blood cell production from the most proliferative subsets more than others., and that 2) these PARP inhibitor effects mobilize long-term stem cells to help meet blood production demands and at the same time create a competitive environment in which stem cells with TP53 or other mutations are favored to outgrow wild- type, but ultimately predisposing patients to bone marrow failure or leukemia. The rationale for this project is that an ever-expanding group of patients are being treated with PARP inhibitors and many experience serious blood and bone marrow toxicities, including development of therapy-related blood cancers, but the mechanism and methods to prevent these serious toxicities are not known. Using mouse and human in vitro and in vivo models, we will test these hypotheses with the following specific aims: 1) Determine how PARP inhibitors disrupt normal hematopoiesis to cause cytopenias; and 2) Determine whether PARP inhibitors create a selective environment and unmask fitness differences in hematopoietic stem and progenitor cells with varying genotypes or are able to mutate these cells on their own. The research proposed in this application is innovative because it is the first study to determine how inhibiting multiple PARP enzymes simultaneously impacts normal hematopoiesis on a mechanistic level. This proposal is significant because it will allow identification of prevention strategies for safe PARP inhibitor use and of new drug targets for improving hematopoiesis via PARP enzyme manipulations.