A New Theranostic System for PET Image Guided Radiotherapy of Cancer

描述（由申请人提供）：传统的癌症治疗缺乏靶向特异性，因此与严重的副作用相关。目前迫切需要高度特异性、靶向性的癌症治疗方法。我们提出了一种新的治疗方法，使用表达细胞表面抗原的间充质干细胞（MSCs）特异性靶向癌细胞的细胞毒性放射性同位素。细胞表面抗原也允许监测靶向间充质干细胞与正电子发射断层扫描。我们将使用86钇-(S)-2-（4-丙烯酰胺苯）- dota (86Y-AABD) PET成像来验证表达细胞表面抗原（DAbR1）的间充质干细胞可以进入肿瘤的假设。随后，我们将用90Y（一种高能β -发射器）标记AABD，以诱导局部和选择性辐射。因此，我们提出了一种新的体内治疗方法。这项工作利用了UCLA研究人员开发的工具和试剂；我们开发了一种细胞膜表达的抗体片段，称为DAbR1，可以用正电子发射断层扫描（PET）检测，使用86Y-AABD。AABD也可以标记90Y用于放射治疗。治疗方法如下：i)将表达DAbR1的MSCs注射到荷瘤小鼠体内。ii)通过86Y-AABD PET显像证实最优数量的DAbR1-MSCs归巢到肿瘤。iii)只有在PET成像确认DAbR1-MSCs对肿瘤的最佳归巢后，才能注射90Y-AABD，以提供选择性肿瘤照射。拟建的研究团队在癌症生物学、分子生物学、生物化学、放射化学、临床前和临床分子成像方面具有卓越的综合能力。在Aim 1中，我们将分析表达DAbR1的MSCs在86Y-AABD PET小鼠肿瘤异种移植物中的运输。我们将确定通过基因工程稳定表达DAbR1是否能保持其正常的增殖和分化。然后，我们将使用86Y-AABD小动物PET/CT评估携带腹部和皮下肿瘤移植的小鼠在多个时间点表达DAbR1的MSCs的全身生物分布。在Aim 2中，我们将测试90Y-AABD在肿瘤浸润表达DAbR1的MSCs后的治疗效果。本提案的最终目标是开发一种新的治疗系统，用于使用放射性药物90Y-AABD进行高度特异性的癌症放射治疗。

DESCRIPTION (provided by applicant): Conventional cancer treatments lack target specificity and are therefore associated with severe side effects. Highly specific, targeted cancer treatment approaches are urgently needed. We propose a novel theranostic approach that uses mesenchymal stem cells (MSCs) expressing a cell surface antigen to specifically target a cytotoxic radioisotope to cancer cells. The cell surface antigen also allows monitoring targeting of MSCs with Positron Emission Tomography. We will test the hypothesis that MSCs expressing a cell surface antigen (DAbR1) can home to tumors using PET imaging with 86 Yttrium- (S)-2-(4-acrylamidobenzyl)-DOTA (86Y-AABD). Subsequently, we will label AABD with 90Y (a high energy beta-emitter) to induce local and selective radiation. Thus, we propose a novel theranostic approach in vivo. This work leverages tools and reagents developed by UCLA investigators; we have developed a cell membrane expressed antibody fragment called DAbR1 that can be detected with positron emission tomography (PET) using 86Y-AABD. AABD can also be labeled with 90Y for radiation treatment. The theranostic will be used as follows: i) MSCs expressing DAbR1 will be injected into tumor bearing mice. ii) Homing of optimized quantities of DAbR1-MSCs to tumors will be confirmed by 86Y-AABD PET imaging. iii) 90Y-AABD will be injected only after PET imaging has confirmed optimal homing of DAbR1-MSCs to tumors to deliver selective tumor irradiation. The team of proposed investigators has combined excellence in cancer biology, molecular biology, biochemistry, radiochemistry, and preclinical and clinical molecular imaging. In Aim 1 we will analyze the trafficking of DAbR1 expressing MSCs to tumor xenografts in mice with 86Y-AABD PET. We will determine whether genetically engineered stably expressing DAbR1 retain their normal proliferation and differentiation. We will then assess the whole-body biodistribution of DAbR1 expressing MSCs at multiple time points with 86Y-AABD small animal PET/CT in mice bearing abdominal and subcutaneous tumor xenografts. In Aim 2 we will test the therapeutic effects of 90Y-AABD following tumor infiltration of DAbR1 expressing MSCs. The ultimate objective of this proposal is the development of a novel theranostic system, to be used for highly specific cancer radiation therapy with the radiopharmaceutical 90Y-AABD.