RECEPTOR TARGETED MOLECULAR IMAGING OF MULTIPLE MYELOMA

描述(由申请人提供)：多发性骨髓瘤(MM)是第二种最常见的血液病诊断癌症，目前的治疗方法仍然无法治愈。18F-脱氧葡萄糖(FDG)/正电子发射断层扫描(PET)、骨骼测量、骨显像和核磁共振成像(MRI)等生物医学成像技术常用于MM患者的分期和治疗后随访。更重要的是，需要对骨骼进行成像，以检测溶骨性病变，以区分MM及其前体状态，如阴燃MM(SMM)和意义不明的单克隆性伽马病(MGUS)。许多有效的化疗药物可用于多发性骨髓瘤患者，但这些药物的最佳使用尚不清楚，绝大多数患者会复发并死于他们的疾病。目前所有可用的成像设备都需要几个月的时间来显示肿瘤反应，因此对于需要对治疗反应进行RAPI评估的临床试验来说，其用处有限。FDG是一种细胞代谢的标志物，对MM的髓内损害的敏感性有限(61%)。骨髓瘤细胞和骨髓环境之间的受体介导的相互作用支持肿瘤的生存。超晚期抗原-4(VLA-4；又称α4β1整合素)是骨髓瘤细胞与骨髓基质黏附的重要介质之一。VLA-4促进骨髓瘤细胞的运输、增殖、分化和耐药。临床上，高水平的VLA-4预示着MM患者预后不良。在这项建议中，我们将开发一种高亲和力和高特异性活性的铜-标记的VLA-4靶向PET放射性药物(64Cu-LP2A)，通过定量成像VLA-4来评估小鼠和人类MM临床前模型中的疾病进展和治疗反应。目标1的目标有两个：a)优化第一代制剂，以提高溶解度和改善药代动力学；b)合成光学和混杂类似物，用于体外和体内结合特异性评估。目的2a将开发一种使用64Cu-LLP2A/PET的成像方法，当骨髓瘤细胞和骨髓瘤引起的骨损伤明显小于现有诊断试验和成像方法时，该方法可以检测到它们。最后，目标2b将重点监测在早期和晚期时间点使用硼替佐米(一种蛋白酶体抑制剂)和唑来膦酸(一种双膦酸类)的治疗反应。这些目标将有助于通过敏感和特异的VLA-4靶向PET成像来准确评估早期疾病和治疗反应。

DESCRIPTION (provided by applicant): Multiple myeloma (MM) is the second most commonly diagnosed hematologic cancer and remains incurable with current therapies. Biomedical imaging techniques such as 18F-fluorodeoxyglucose (FDG)/Positron Emission Tomography (PET), skeletal survey, bone scintigraphy and Magnetic Resonance Imaging (MRI) are routinely used for staging and post-treatment follow up in MM patients. More importantly, imaging of the skeleton with the aim of detecting lytic bone lesions is needed to discriminate MM from its precursor states such as smoldering MM (sMM) and monoclonal gammopathy of undetermined significance (MGUS). Many effective chemotherapy agents are available for MM patients, but the optimal use of these agents is not clear and a vast majority of patients relapse and die from their disease. All currently available imaging modalities take months to demonstrate tumor responses and therefore are of limited utility for clinical trials requiring rapi evaluation of treatment responses. FDG is a marker of cell metabolism that has limited sensitivity (61%) for intramedullary lesions in MM. Receptor-mediated interactions between myeloma cells and BM milieu support tumor survival. Very late antigen-4 (VLA-4; also called alpha4beta1 integrin) is one of the critical mediators of myeloma cell adhesion to the BM stroma. VLA-4 promotes myeloma cell trafficking, proliferation, differentiation and drug resistance. Clinically, high-levels of VLA-4 predict a poor prognosis in MM patients. In this proposal, we will develop a high-affinity and high-specific activity, copper-64 labeled VLA-4 targeted PET radiopharmaceutical (64Cu-LLP2A) to assess disease progression and response to treatment in pre-clinical models of mouse and human MM by quantitatively imaging VLA-4. The goal of aim 1 is twofold: a) to optimize the first-generation agent to enhance solubility and improve pharmacokinetics; and b) to synthesize optical and scrambled analogs for in vitro and in vivo binding specificity evaluations. Aim 2a will develop an imaging method using 64Cu- LLP2A/PET that can detect myeloma cells and myeloma induced bone lesions when they are significantly smaller than those currently detected with existing diagnostic tests and imaging methods. Finally, Aim 2b will focus on the monitoring of therapeutic responses using bortezomib (a proteasome inhibitor) and zoledronic acid (a bisphosphonate) at early and late time points. These aims will help in the accurate assessment of early stage disease and treatment response by sensitive and specific VLA-4 targeted PET imaging.