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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：尽管具有侵略性的多模式治疗方案，但大多数患有复发或原发性固体瘤的儿科患者的预后较差，在过去的三十年中没有显着改变。外束辐射疗法是大多数实体瘤治疗的一种工具部分，但在传播疾病的情况下的适用性有限。专门将电离辐射到肿瘤细胞的可注射化合物具有有效治疗转移性疾病的潜力，但是对于大多数小儿肿瘤而言，这些药物不存在。 CLR1404是一种新型的，广泛的靶向肿瘤的磷脂醚类似物，它通过专门的质膜微域（称为脂质筏）进入癌细胞。恶性细胞包含比正常细胞更高的脂质筏，导致药物在细胞内和细胞内首选积累细胞机制。在啮齿动物和非人类私人的临床前毒理学研究表明，毒性非常有利。我们的初步数据表明，在药物保留健康组织时，在各种小儿肿瘤系和体内的CLR1404显着摄取。 CLR1404已用于肿瘤选择性PET/CT成像（124i-CLR1404）和肿瘤特异性放疗（131i-CLR1404），并已在我们机构的成人癌症中进行临床试验。我们假设放射碘化的衍生物131i-CLR1404是一种适合小儿固体癌分子放疗的合适药物。我们的申请旨在提供必要的临床前数据来启动小儿试验。 Therefore, we will investigate this drug in mouse xenograft models of four pediatric tumors with particularly poor survival in disseminated disease or relief (neuroblastoma, 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复杂的蒙特 - 卡洛仿真作为小儿临床研究的有用工具。在辐射损伤后的修复机制中，质量剂量高于放射疗法，并且可能是无线电敏感的。