A cancer-targeted phospholipid ether analog for molecular radiotherapy of pediatric solid tumors

用于儿童实体瘤分子放射治疗的癌症靶向磷脂醚类似物

• 批准号: 9064105
• 负责人: Bryan Patrick Bednarz
• 金额: $ 16.64万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-06 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9064105
• 关键词: Adult; Biodistribution; Biological; Cell membrane; Child; Childhood; Childhood Solid Neoplasm; Clinical; Clinical Data; Clinical Protocols; Clinical Research; Clinical Trials; Combined Modality Therapy; Data; Discipline of Nuclear Medicine; Disease; Dose; Evaluation; Ewings sarcoma; External Beam Radiation Therapy; FDA approved; Generations; Goals; Guanidines; Health; Image; Immunohistochemistry; In Vitro; Injectable; Institution; Ionizing radiation; Isotopes; Malignant Childhood Neoplasm; Malignant Neoplasms; Measurable; Medical; Membrane Microdomains; Methods; Modeling; Molecular; Monte Carlo Method; Mus; Neuroblastoma; Normal Cell; PET/CT scan; Pathway interactions; Patients; Pediatric Neoplasm; Pediatric Oncology; Pharmaceutical Preparations; Phase; Phospholipid Ethers; Physics; Play; Pre-Clinical Model; Radiation; Radiation Injuries; Radiation Oncology; Radiation therapy; Radiation-Sensitizing Agents; Radio; Radioactive; Radioactive Iodine; Radioisotopes; Radiolabeled; Radiopharmaceuticals; Radiosensitization; Refractory; Regimen; Relapse; Research; Research Personnel; Rhabdomyosarcoma; Rodent; Rodent Model; Role; Scanning; Solid; Solid Neoplasm; Survival Rate; Testing; Therapeutic; Tissues; Toxic effect; Tracer; Translating; Translational Research; Tumor Cell Line; Universities; Variant; Wisconsin; Xenograft Model; Xenograft procedure; advanced disease; alternative treatment; analog; cancer cell; cancer therapy; cell growth; clinical efficacy; clinical toxicology; dosimetry; extracellular; human subject; improved; in vivo; killings; metaiodobenzylguanidine; neoplastic cell; nonhuman primate; novel; osteosarcoma; outcome forecast; palliation; palliative; pediatric patients; peripheral blood; pre-clinical; protocol development; quantitative imaging; radiosensitizing; radiotracer; repaired; response; sarcoma; scaffold; small molecule; tool; treatment response; treatment strategy; tumor; tumor xenograft; uptake

 DESCRIPTION (provided by applicant): Despite aggressive multimodality therapy regimen, most pediatric patients with relapsed or primary metastatic solid tumors have a very poor prognosis which has not significantly changed in the past three decades. External beam radiation therapy is an instrumental part of treatment of most solid tumors, but has a limited applicability in the setting of disseminated disease. Injectable compounds that specifically deliver ionizing radiation to tumor cells have the potential to effectively treat metastatic diseas, but for most pediatric tumors those drugs do not exist. CLR1404 is a novel, broadly tumor-targeting phospholipid ether analog which enters cancer cells via specialized plasma membrane micro-domains called lipid rafts. Malignant cells contain much higher amounts of lipid rafts than do normal cells, resulting in the preferential accumulation of the drug in extra- and intracellular cell membranes. Pre-clinical toxicology studies in rodents and non-human primates have demonstrated a very favorable toxicity profile. Our preliminary data demonstrate significant uptake of CLR1404 in various pediatric tumor lines in vitro and in vivo while the drug is sparing healthy tissue. CLR1404 has been radio-iodinated for tumor-selective PET/CT imaging (124I-CLR1404) and tumor-specific radiotherapy (131I-CLR1404) and has entered clinical trials in adult cancers at our institution. We hypothesize that the radio-iodinated derivative, 131I-CLR1404, is a suitable drug for molecular radiotherapy of pediatric solid cancers. Our application aims at providing the necessary pre-clinical data to initiate a pediatric trial. Therefore, we will investigate this drug in mouse xenograft models of four pediatric tumors with particularly poor survival in disseminated disease or relapse (neuroblastoma, rhabdomyosarcoma, osteo-sarcoma and Ewing sarcoma). In neuroblastoma, we will compare 131I-CLR1404 to an established radioactive drug for imaging and treatment, 131I-MIBG (m-iodo-benzyl-guanidine). We will perform uptake and dosimetry studies using sophisticated Monte-Carlo-Simulation as a useful tool for pediatric clinical studies. We will evaluate tumor response to treatment with 131I-CLR1404 in mouse xenograft models to establish proof-of- principle for the in vivo activity of this novel molecular radio-therapeutic compound and provide the rationale for clinical protocol development. The non-radioactive compound 127I-CLR1404 interferes with pathways crucial in repair mechanisms after radiation injury in mass doses higher than used for radiotherapy and may act as a radio-sensitizer. Therefore, we will investigate whether combination therapy of 127I-CLR1404 with 131I-CLR1404 or 131I-MIBG leads to improved anti-cancer effects in vivo. Extensive pre- clinical data exist with CLR1404 for adult cancers and adult clinical trials have begun at our institution. We are confident that results obtained with our application that would support evaluation of 131I-CLR1404 in pediatric solid tumors can be translated into a clinical trial within 2-3 years.

 描述（由申请人提供）：尽管采用了积极的多模式治疗方案，但大多数复发性或原发性转移性实体瘤儿科患者的预后非常差，在过去三十年中没有显著变化。外照射放射治疗是大多数实体瘤治疗的工具部分，但在播散性疾病中的适用性有限。专门向肿瘤细胞提供电离辐射的注射化合物有可能有效治疗转移性疾病，但对于大多数儿科肿瘤来说，这些药物并不存在。 CLR 1404是一种新型的、广泛靶向肿瘤的磷脂醚类似物，其通过称为脂筏的专门质膜微结构域进入癌细胞。恶性细胞比正常细胞含有更大量的脂筏，导致药物在细胞外和细胞内的优先积累。 细胞膜在啮齿动物和非人灵长类动物中进行的临床前毒理学研究已证明具有非常有利的毒性特征。我们的初步数据表明，CLR 1404在体外和体内的各种儿科肿瘤细胞系中有显著的摄取，而药物不影响健康组织。CLR 1404已被放射性碘标记用于肿瘤选择性PET/CT成像（124 I-CLR 1404）和肿瘤特异性放疗（131 I-CLR 1404），并已进入我们机构的成人癌症临床试验。 我们假设放射性碘化衍生物131 I-CLR 1404是一种适合用于儿童实体癌分子放射治疗的药物。我们的申请旨在提供必要的临床前数据，以启动儿科试验。因此，我们将在四种小儿肿瘤（神经母细胞瘤、横纹肌肉瘤、骨肉瘤和尤文肉瘤）的小鼠异种移植模型中研究这种药物，这些肿瘤在播散性疾病或复发中的存活率特别低。在神经母细胞瘤中，我们将比较131 I-CLR 1404与已建立的用于成像和治疗的放射性药物131 I-MIBG（间碘苄基胍）。我们将使用复杂的蒙特-卡罗模拟作为儿科临床研究的有用工具进行摄取和剂量测定研究。我们将在小鼠异种移植模型中评价肿瘤对131 I-CLR 1404治疗的反应，以建立这种新型分子放射治疗化合物体内活性的原理证明，并为临床方案开发提供依据。非放射性化合物127 I-CLR 1404以高于用于放射治疗的质量剂量干扰辐射损伤后修复机制中至关重要的途径，并且可以充当放射增敏剂。因此，我们将研究127 I-CLR 1404与131 I-CLR 1404或131 I-MIBG的组合疗法是否导致体内抗癌效果的改善。存在CLR 1404用于成人癌症的广泛临床前数据，并且成人临床试验已经在我们机构开始。我们相信，我们的应用程序获得的结果将支持131 I-CLR 1404在儿科实体瘤中的评价，可以在2-3年内转化为临床试验。