PARP-1 as a novel target for alpha-particle therapy in high-risk Neuroblastoma

高危神经母细胞瘤(NB)是一种致命的儿童恶性肿瘤，长期存活率不到20%。当前 治疗方法依赖于强化化疗、放射治疗和放射治疗。尽管它的高 复发率，高危NB是一种对治疗性放射性药物敏感的疾病。这有 已经在多项临床试验中得到证明，在这些试验中，释放β的碘-131-间碘苄基胍 ([131I]MIBG)在所有受试单药中显示出最高的应答率。然而，身体上的 β颗粒的特性使其在微转移疾病的诊断中效率低下。这是 尤其与高危NB有关，因为已经假设复发的NB主要是由残留的 骨髓中的微转移疾病。较短的路径长度和较高的相对生物有效性 α粒子有可能克服β粒子的限制，根除微转移 疾病。聚(ADP-核糖)聚合酶1具有多种生物学功能，专门位于 细胞核，直接在染色质上。此外，PARP-1在高危NB和 结合其亚细胞定位，它是α粒子治疗的一个独特的治疗靶点。穿过 Astatine-211对小分子PARP抑制剂的官能化研究 PARP-1靶向α发射放射治疗[(MM4)]。我们假设将阿尔法粒子 通过靶向肿瘤中差异PARP-1表达模式直接进入NB型癌细胞基因组 与非癌组织相比，在选择性地摧毁宏微肿瘤方面将是安全和有效的，而不是 正常组织。通过这项提议，我们将充分描述MM4细胞的致命性和潜力 用最先进的CRISPR/Cas9基因组编辑技术研究高危NB的抗性机制。在……里面 此外，使用患者来源的NB异种移植(PDX)模型，我们将执行 NB PDX模型和新的图像引导治疗和生存研究。

High-risk neuroblastoma (NB) is a deadly pediatric malignancy with less than 20% long term survival. Current therapeutic approaches rely on intensive chemotherapy, radiotherapy and radiotherapeutics. Despite its high relapse rate, high risk NB is a radiosensitive disease amenable to therapeutic radiopharmaceuticals. This has been shown clinically in multiple trials where the beta-emitting Iodine-131-metaiodobenzylguanidine ([131I]MIBG) showed the highest response rate of any tested single agent. However, the physical characteristics of beta particles makes them inefficient in the setting of micrometastatic disease. This is particularly relevant to high risk NB as it has been postulated that relapsed NB is caused primarily by residual micrometastatic disease in the bone marrow. The short path length and high relative biological effectiveness of alpha particles have the potential to overcome the limitations of beta particles and eradicate micrometastatic disease. Poly(ADP-ribose) Polymerase 1 has a variety of biological functions and is specifically located in the nucleus, directly on the chromatin. Furthermore, PARP-1 was shown to be overexpressed in high-risk NB and combined with its subcellular localization it is a unique therapeutic target for alpha-particle therapy. Through the functionalization of a small molecule PARP inhibitor with astatine-211 (²¹¹At), we have developed a novel PARP-1 targeted alpha-emitting radiotherapeutic [(²¹¹At]MM4). We hypothesize that delivering alpha-particles directly to the genome of NB cancer cells through targeting differential PARP-1 expression patterns in cancer vs. non-cancer tissue will be safe and effective at selectively destroying macro- and microtumors while sparing normal tissue. Through this proposal, we will fully characterize [²¹¹At]MM4 for cellular lethality and potential mechanisms of resistance in high-risk NB using state-of-the-art CRISPR/Cas9 genome editing technology. In addition, using patient derived xenograft (PDX) models of NB we will perform the molecular characterization of NB PDX models and novel image guided therapy and survival studies.