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，新诊断的GBM患者在手术/放疗组的中位生存期仅为12.1个月，在替莫唑胺治疗组的中位生存期为14.6个月。尽管最近在诊断和治疗技术方面取得了进展，但恶性胶质瘤患者的预后仍然很差。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，肿瘤浸润周围正常脑的真实程度往往不能充分表征。此外，在治疗后，常规MRI在区分假性进展和治疗性坏死与肿瘤复发方面也有局限性，这可能导致假阳性结果，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的NM404作为一种消肿剂，用于检测和治疗各种实体肿瘤，包括脑肿瘤。NM404是一种精炼的第二代磷脂醚类似物，其特点是在50/52人异种移植物、自发和转基因临床前肿瘤模型（包括胶质瘤）中优先吸收肿瘤和延长肿瘤保留时间。NM404选择性摄取的机制基础是由于选择性插入脂筏并最终内化到细胞中。与正常细胞相比，恶性细胞的脂筏数量大大增加。用治疗同位素碘-131 （NM404）标记后，在十几个小鼠的人类异种移植肿瘤模型中单次注射后，寿命显著延长。本成像方案的目的是首先优化124I-NM404在恶性脑肿瘤患者中的PET成像参数，然后将该药物的肿瘤敏感性和特异性与当前最先进的MRI成像技术和病理进行比较。如果NM404 PET/CT结果在准确确定肿瘤浸润的真实程度方面优于MRI，那么这项新技术可用于指导术前术中活检，改进手术和放疗计划，监测治疗反应，区分假进展或放射性坏死与真正的肿瘤复发。这一新的诊断信息将有助于显著提高当前治疗下患者的生存率。此外，如果与新的131I-NM404全身放疗相结合，患者的生存可能会显着提高。

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.