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

 描述(申请人提供)：尽管采用了积极的多种治疗方案，但大多数复发或原发转移实体瘤的儿科患者预后非常差，这一点在过去30年中没有明显改变。体外放射治疗是治疗大多数实体肿瘤的辅助手段，但在播散性疾病中的适用性有限。专门向肿瘤细胞传递电离辐射的可注射化合物具有有效治疗转移性疾病的潜力，但对于大多数儿科肿瘤来说，这些药物并不存在。CLR1404是一种新型的、广泛靶向肿瘤的磷脂醚类似物，它通过称为脂筏的特殊质膜微域进入癌细胞。恶性细胞含有比正常细胞高得多的脂筏，导致药物在细胞外和细胞内优先聚集。 细胞膜。在啮齿动物和非人类灵长类动物中进行的临床前毒理学研究表明，该药具有非常有利的毒性。我们的初步数据显示，CLR1404在体外和体内的各种儿科肿瘤株中有显著的摄取，而该药物节省了健康组织。CLR1404已被放射性碘标记，用于肿瘤选择性PET/CT成像(124I-CLR1404)和肿瘤特异性放射治疗(131I-CLR1404)，并已进入我所成人癌症的临床试验。我们推测131I-CLR1404是一种适合于儿童实体瘤分子放射治疗的药物。我们的应用程序旨在为启动儿科试验提供必要的临床前数据。因此，我们将在四种在播散性疾病或复发(神经母细胞瘤、横纹肌肉瘤、骨肉瘤和尤文肉瘤)中存活率特别低的儿童肿瘤的小鼠异种移植模型中研究该药物。在神经母细胞瘤中，我们将比较131I-CLR1404和已有的用于成像和治疗的放射性药物131I-MIBG(间碘-苯基胍)。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来进行摄取和剂量学研究。我们将在小鼠异种移植模型中评估131I-CLR1404治疗肿瘤的反应，为这种新型分子放射治疗化合物的体内活性建立原理证明，并为临床方案的开发提供理论基础。非放射性化合物127I-CLR1404干扰辐射损伤后修复机制中至关重要的途径，其质量剂量高于放射治疗所用的剂量，并可能作为放射增敏剂。因此，我们将研究127I-CLR1404与131I-CLR1404或131I-MIBG在体内联合治疗是否能提高抗癌效果。CLR1404用于成人癌症的大量临床前数据已经存在，我们机构已经开始成人临床试验。我们相信，通过我们的应用获得的结果将支持131I-CLR1404在儿童实体肿瘤中的评估，并将在2-3年内转化为临床试验。

 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.