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

描述(申请人提供)：由几个国际脑肿瘤和放射治疗小组进行的大型多中心试验表明，接受手术/放射治疗的新诊断的GBM患者的中位生存期仅为12.1个月，而加入替莫唑胺治疗后的中位生存期为14.6个月。尽管诊断和治疗技术最近取得了进步，但恶性胶质瘤患者的这种令人沮丧的预后仍然存在。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，肿瘤向周围正常脑组织的真实浸润程度往往也不能得到充分的表征。此外，在治疗后，常规MRI在区分假性进展和治疗坏死与肿瘤复发方面也存在局限性，这可能会导致假阳性结果，从而可能使患者接受不必要的程序和/或治疗。显然，需要对这些患者采取新的诊断和管理策略。我们的实验室正在开发放射性碘化NM404作为一种治疗药物，用于检测和治疗各种实体肿瘤，包括脑瘤。NM404是一种精制的第二代磷脂醚类似物，在50/52人异种移植瘤、自发性和转基因临床前肿瘤模型(包括胶质瘤)中具有优先摄取肿瘤和延长肿瘤滞留时间的特点。NM404选择性摄取的机制基础是选择性地插入到脂筏中，从而内化到细胞中。现已知，与正常细胞相比，恶性细胞中的脂筏数量大大增加。当标记治疗同位素碘-131时，NM404在12个人异种移植瘤小鼠模型中单次注射后，显著延长了生命。这一成像方案的目标是首先优化124I-NM404在恶性脑瘤患者中的PET成像参数，然后将该试剂的肿瘤敏感性和特异性与当前最先进的MRI成像技术和病理进行比较。如果NM404PET/CT结果在准确确定肿瘤浸润的真实范围方面优于MRI，那么这项新技术可以用于指导术前或术中活组织检查，改进手术和放射治疗计划，监测治疗反应，并将假性进展或放射性坏死与真正的肿瘤复发区分开来。这一新的诊断信息可以帮助使用当前的治疗方法显著提高患者的存活率。此外，如果结合新的131I-NM404系统放射治疗，患者的存活率可能会显著提高。 公共卫生相关性：该项目调查了一种新的肿瘤显像剂NM404的用途，以更准确地描述人类恶性脑瘤的特征。如果NM404在确定恶性脑瘤的特征方面优于目前的诊断方法，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.