PET/CT Imaging of Malignant Brain Tumors with 124I-NM404

描述（由申请人提供）：一项由几个国际脑肿瘤和放疗组进行的大型多中心试验表明，新诊断GBM患者的中位生存期仅为12.1个月（手术/放疗）和14.6个月（添加替莫唑胺治疗）。尽管最近诊断和治疗技术取得了进展，但恶性胶质瘤患者的预后仍然令人沮丧。即使使用先进的MRI脉冲序列和PET放射性药物，在手术切除和放射治疗之前，肿瘤浸润到周围正常脑中的真实程度通常不充分。此外，治疗后，常规MRI在区分假进展和治疗坏死与肿瘤复发方面也有局限性，这可能导致假阳性结果，可能使患者接受不必要的手术和/或治疗。显然，这些患者需要新的诊断和管理策略。我们的实验室正在开发放射性碘标记的NM 404作为一种诊断剂，用于检测和治疗各种实体瘤，包括脑肿瘤。NM 404是一种精制的第二代磷脂醚类似物，其特征是在50/52人类异种移植、自发和转基因临床前肿瘤模型（包括神经胶质瘤）中优先肿瘤吸收和延长肿瘤保留。选择性摄取NM 404的机制基础是由于选择性插入到脂筏中并由此内化到细胞中。现在已知恶性细胞与正常细胞相比具有大量增加的脂筏。当用治疗同位素碘-131标记时，NM 404在小鼠的十几种人类异种移植肿瘤模型中单次注射后产生了显著的生命延长。该成像方案的目标是首先优化恶性脑肿瘤患者124 I-NM 404的PET成像参数，然后将该药剂的肿瘤敏感性和特异性与当前最先进的MRI成像技术和病理学进行比较。如果NM 404 PET/CT结果证明在准确定义肿瘤浸润的真实程度方面上级MRI，那么这种新技术可用于指导术前或术中活检，改善手术和放疗计划，监测治疗反应，并区分假性进展或放射性坏死与真实肿瘤复发。这种新的诊断信息可以帮助显着提高患者的生存与目前的治疗。此外，如果再加上新的131 I-NM 404全身放疗，患者的生存率可能会显着提高。 公共卫生相关性：该项目研究了一种新的肿瘤显像剂NM 404的效用，以更准确地表征人类恶性脑肿瘤。如果NM 404在表征恶性脑肿瘤方面上级目前的诊断方法，那么它将改善脑癌患者的预后。

DESCRIPTION (provided by applicant): A large multicenter trial performed by several international brain tumor and radiotherapy groups demonstrated a median survival in patients with newly diagnosed GBM of only 12.1 months with surgery/radiotherapy and 14.6 months when temozolamide therapy was added. This dismal prognosis for patients with malignant gliomas remains despite recent advances in diagnostic and therapeutic techniques. Even with the use of advanced MRI pulse sequences and PET radiopharmaceuticals, the true extent of tumor infiltration into surrounding normal brain is often inadequately characterized prior to surgical resection and radiation treatment. Moreover, following treatment, conventional MRI also has limitations in distinguishing pseudoprogression and treatment necrosis from tumor recurrence which can lead to false positive findings that may subject patients to unnecessary procedures and/or treatments. Clearly, new diagnostic and management strategies are needed for these patients. Our lab is developing radioiodinated NM404 as a diapeutic agent for the detection and treatment of a wide variety of solid tumors, including brain tumors. NM404 is a refined, second-generation, phospholipid ether analog that is characterized by preferential tumor uptake and prolonged tumor retention in 50/52 human xenograft, spontaneous and transgenic preclinical tumor models, including gliomas. The mechanistic basis for the selective uptake of NM404 is due to selective insertion into lipid rafts and resultant internalization into the cell. Malignant cells are now known to have greatly increased amounts of lipid rafts compared to normal cells. When labeled with the therapy isotope iodine-131, NM404, has produced significant prolongation of life following a single injection in a dozen human xenograft tumor models in mice. The goal of this imaging proposal is to first optimize the PET imaging parameters of 124I-NM404 in malignant brain tumor patients and then compare the tumor sensitivity and specificity of this agent with current state-of-the-art MRI imaging techniques and pathology. If NM404 PET/CT results prove superior to MRI in accurately defining the true extent of tumor infiltration, then this new technique may be used to guide preor intra-surgical biopsies, improve surgical and radiotherapy planning, monitor treatment response, and differentiate pseudoprogression or radiation necrosis from true tumor recurrence. This new diagnostic information could help significantly improve patient survival with current therapies. Additionally, if coupled with new 131I-NM404 systemic radiotherapy, patient survival may be dramatically improved. PUBLIC HEALTH RELEVANCE: This project investigates the utility of a new tumor imaging agent, NM404, to more accurately characterize malignant brain tumors in humans. If NM404 proves superior to current diagnostic methodologies in characterizing malignant brain tumors, then it will result in improved outcomes for patients with brain cancer.