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点特异性，因此与严重的副作用有关。迫切需要高度特异性、靶向的癌症治疗方法。我们提出了一种新的治疗诊断方法，该方法使用表达细胞表面抗原的间充质干细胞（MSC）来特异性靶向癌细胞的细胞毒性放射性同位素。细胞表面抗原还允许用正电子发射断层扫描监测MSC的靶向。我们将使用86钇-（S）-2-（4-丙烯酰胺苄基）-DOTA（86 Y-AABD）的PET成像来检验表达细胞表面抗原（DAbR 1）的MSC可以归巢到肿瘤的假设。随后，我们将用90 Y（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治疗诊断方法在体内。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;我们开发了一种细胞膜表达的抗体片段，称为DAbR 1，可以使用86 Y-AABD用正电子发射断层扫描（PET）检测。AABD也可以用90 Y标记用于放射治疗。治疗诊断剂将如下使用：i）将表达DAbRl的MSC注射到荷瘤小鼠中。ii）将通过86 Y-AABD PET成像确认优化量的DAbR 1-MSC向肿瘤的归巢。iii）仅在PET成像已经证实DAbR 1-MSC最佳归巢至肿瘤以递送选择性肿瘤照射之后，才注射90 Y-AABD。该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成就。在目的1中，我们将用86 Y-AABD PET分析表达DAbR 1的MSC向小鼠中的肿瘤异种移植物的运输。我们将确定基因工程稳定表达DAbR 1是否保留其正常增殖和分化。然后，我们将在多个时间点用86 Y-AABD小动物PET/CT在携带腹部和皮下肿瘤异种移植物的小鼠中评估表达DAbRl的MSC的全身生物分布。在目的2中，我们将测试在表达DAbRl的MSC的肿瘤浸润后90 Y-AABD的治疗效果。该提案的最终目标是开发一种新型治疗诊断系统，用于放射性药物90 Y-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.