RECEPTOR TARGETED MOLECULAR IMAGING OF MULTIPLE MYELOMA

描述（由申请人提供）：多发性骨髓瘤（MM）是第二种最常诊断的血液系统癌症，目前的治疗方法仍无法治愈。生物医学成像技术，如18 F-氟脱氧葡萄糖（FDG）/正电子发射断层扫描（PET）、骨骼检查、骨密度成像和磁共振成像（MRI），通常用于MM患者的分期和治疗后随访。更重要的是，需要以检测溶骨性病变为目的的骨骼成像，以区分MM与其前驱状态，如阴燃MM（sMM）和意义不明的单克隆丙种球蛋白病（MGUS）。许多有效的化疗药物可用于MM患者，但这些药物的最佳使用尚不清楚，绝大多数患者复发并死于疾病。所有目前可用的成像方式需要数月时间来证明肿瘤反应，因此对于需要rapi评估治疗反应的临床试验的实用性有限。FDG是细胞代谢的标志物，其对MM中髓内病变的敏感性有限（61%）。骨髓瘤细胞和BM环境之间的受体介导的相互作用支持肿瘤存活。极晚期抗原-4（VLA-4;也称为α 4 β 1整联蛋白）是骨髓瘤细胞粘附至BM基质的关键介质之一。VLA-4促进骨髓瘤细胞运输、增殖、分化和耐药性。临床上，高水平的VLA-4预测MM患者的预后不良。在该提案中，我们将开发一种高亲和力和高比活度的铜-64标记的VLA-4靶向PET放射性药物（64 Cu-LLP 2A），通过对VLA-4进行定量成像，在小鼠和人MM的临床前模型中评估疾病进展和治疗反应。目的1的目标是双重的：a）优化第一代试剂以增强溶解度并改善药代动力学;和B）合成用于体外和体内结合特异性评价的光学和乱序类似物。目标2a将开发一种使用64 Cu-LLP 2A/PET的成像方法，当骨髓瘤细胞和骨髓瘤诱导的骨病变显著小于目前用现有诊断测试和成像方法检测到的那些时，该成像方法可以检测骨髓瘤细胞和骨髓瘤诱导的骨病变。最后，目标2b将侧重于监测使用硼替佐米（一种蛋白酶体抑制剂）和唑来膦酸（一种双膦酸盐）在早期和晚期时间点的治疗反应。这些目标将有助于通过敏感和特异性的VLA-4靶向PET成像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.