A New Theranostic System for PET Image Guided Radiotherapy of Cancer

描述(申请人提供)：传统的癌症治疗缺乏靶点特异性，因此与严重的副作用有关。迫切需要高度具体、有针对性的癌症治疗方法。我们提出了一种新的治疗方法，利用表达细胞表面抗原的间充质干细胞(MSCs)特异性地将细胞毒性放射性同位素靶向癌细胞。细胞表面抗原还可以通过正电子发射断层扫描监测MSCs的靶向。我们将使用86Y-(S)-2-(4-丙烯酰胺基苯甲基)-DOTA(86Y-AABD)的正电子发射计算机断层成像来验证这样的假设，即表达细胞表面抗原(DAbR1)的MSCs可以在肿瘤中定位。随后，我们将用90Y(一种高能β发射体)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。这项工作利用了加州大学洛杉矶分校研究人员开发的工具和试剂；我们开发了一种名为DAbR1的细胞膜表达抗体片段，可以使用86Y-AABD通过正电子发射断层扫描(PET)进行检测。AABD也可以标记90Y进行放射治疗。治疗的用途如下：i)将表达DAbR1的MSCs注射到荷瘤小鼠体内。Ii)86Y-AABD PET成像将证实优化数量的DAbR1-MSCs与肿瘤的归巢。Iii)只有在PET成像确认DAbR1-MSCs对肿瘤的最佳归巢以提供选择性肿瘤照射后，才会注射90Y-AABD。拟议的研究团队结合了癌症生物学、分子生物学、生物化学、放射化学以及临床前和临床分子成像方面的卓越表现。目的1利用86Y-AABD正电子发射计算机断层扫描，分析表达DAbR1的骨髓间充质干细胞在小鼠移植瘤中的转运。我们将确定稳定表达DAbR1的基因工程是否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评估在多个时间点表达DAbR1的MSCs在荷有腹部和皮下移植瘤的小鼠体内的生物分布。在目的2中，我们将检测90Y-AABD对DAbR1表达的MSCs侵袭肿瘤的治疗作用。这项建议的最终目标是开发一种新型的治疗系统，用于放射性药物90Y-AABD的高度特异性癌症放射治疗。

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.