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

PARP-1作为高危神经母细胞瘤α粒子治疗的新靶点

• 批准号: 10375475
• 负责人: Daniel A. Pryma
• 金额: $ 57.71万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375475
• 关键词: Address; Affect; Alpha Particles; Astatine; Beta Particle; Binding; Biodistribution; Biological; Biological Assay; Biological Process; Bone Marrow; CRISPR screen; CRISPR/Cas technology; Cause of Death; Cell Death; Cell Line; Cell Nucleus; Cell Survival; Cells; Characteristics; Child; Childhood; Chromatin; Clinical; DNA Damage; DNA Repair; Deposition; Disease; Dose; Drug Targeting; Enzymes; Evaluation; Feedback; Genome; Genotoxic Stress; Guide RNA; Histology; Human; I131 isotope; Immunohistochemistry; In Vitro; Inflammation; Length; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Metabolism; Microscopic; Microscopy; Modeling; Molecular; Neuroblastoma; Normal tissue morphology; Patients; Pattern; Pharmacology; Phosphotransferases; Poly(ADP-ribose) Polymerases; Positron-Emission Tomography; Property; Proteins; RNA library; Radiation; Radiation Tolerance; Radiation therapy; Radioisotopes; Radiopharmaceuticals; Regimen; Relapse; Relative Biological Effectiveness; Residual state; Resistance; Role; Solid Neoplasm; Sp1 Transcription Factor; Technology; Testing; Therapeutic; Tissue Microarray; Tissues; Toxic effect; Up-Regulation; Western Blotting; X-Ray Computed Tomography; Xenograft Model; biomarker discovery; cancer cell; chemotherapy; companion diagnostics; cytotoxicity; design; genome editing; high risk; image guided therapy; improved; improved outcome; in vivo; in vivo evaluation; inhibitor; innovation; mRNA Expression; metaiodobenzylguanidine; microPET/CT; neuroblastoma cell; noradrenaline transporter; novel; novel therapeutics; overexpression; particle; particle therapy; patient derived xenograft model; physical property; resistance mechanism; response; small molecule; targeted radiotherapeutic; therapeutic target; treatment response; tumor

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.

高危神经母细胞瘤（NB）是一种致命的儿科恶性肿瘤，长期生存率低于20%。电流 治疗方法依赖于强化化疗、放疗和放射治疗剂。尽管其高 复发率高、风险高的NB是一种放射敏感性疾病，可以用治疗性放射性药物治疗。这 在多项临床试验中显示，β-发射碘-131-间碘苄胍 （[131 I]MIBG）显示任何测试的单一药剂的最高响应率。但是，物理 β粒子的特性使得它们在微转移性疾病的情况下效率低下。这是 尤其与高风险NB相关，因为已经假设复发性NB主要由残留的 骨髓微转移性疾病短的路径长度和高的相对生物有效性， α粒子有可能克服β粒子的局限性， 疾病聚ADP-核糖聚合酶1具有多种生物学功能，并且特异性地定位于 直接在染色质上。此外，PARP-1在高风险NB中过表达， 结合其亚细胞定位，它是α粒子治疗的独特治疗靶点。通过 通过对小分子PARP抑制剂的功能化，我们开发了一种新的 PARP-1靶向α-发射放射性核素[（<$At] MM 4）。我们假设释放阿尔法粒子 通过靶向癌症中的差异PARP-1表达模式直接靶向NB癌细胞的基因组 vs.非癌组织将安全有效地选择性破坏大肿瘤和小肿瘤， 正常组织通过这项提案，我们将充分表征[At] MM 4的细胞致死性和潜力， 使用最先进的CRISPR/Cas9基因组编辑技术研究高风险NB的耐药机制。在 此外，使用NB的患者来源的异种移植物（PDX）模型，我们将进行以下的分子表征： NB PDX模型和新的图像引导治疗和生存研究。