A New Theranostic System for PET Image Guided Radiotherapy of Cancer

一种用于 PET 图像引导癌症放射治疗的新型治疗诊断系统

基本信息

批准号：
8572008
负责人：
JOHANNES CZERNIN
金额：
$ 16.75万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8572008
关键词：
90Y Abdomen Adipocytes Adverse effects Affect Animals Antibodies Binding Biochemistry Biodistribution Cancer Biology Cancer Patient Cell membrane Cell surface Cells Chondrocytes Clinical Development Diagnosis Diagnostic Imaging Drug Kinetics Engineering External Beam Radiation Therapy Genes Genetic Engineering Goals Hepatic artery Home environment Homing Human Image Immunoglobulin Fragments Infiltration Intra-abdominal Kinetics Label Lead Liver Malignant Neoplasms Measurement Mesenchymal Stem Cells Microspheres Molecular Biology Monitor Mus Neoplasm Metastasis Outcome Patients Positron-Emission Tomography Pre-Clinical Model Primary Neoplasm Public Health Radiation Radiation therapy Radio Radiochemistry Radioimmunoconjugate Radioisotopes Radiopharmaceuticals Reagent Research Personnel Resectable Site Specificity Surface Antigens System Testing Therapeutic Therapeutic Effect Time Toxic effect Translating Translations Tumor Volume Validation Work Xenograft procedure Yttrium base cancer cell cancer radiation therapy cancer therapy chemotherapy cytotoxic cytotoxicity imaging probe improved in vivo infancy intravenous injection irradiation killings molecular imaging novel pre-clinical public health relevance response soft tissue subcutaneous theranostics tool trafficking tumor tumor xenograft yttria

项目摘要

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.

描述（由申请人提供）：传统的癌症治疗缺乏靶点特异性，因此会产生严重的副作用。迫切需要高度特异性、有针对性的癌症治疗方法。我们提出了一种新颖的治疗诊断方法，该方法使用表达细胞表面抗原的间充质干细胞（MSC）将细胞毒性放射性同位素特异性靶向癌细胞。细胞表面抗原还允许通过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-丙烯酰氨基苯甲基)-DOTA (86Y-AABD) 进行 PET 成像，测试表达细胞表面抗原 (DAbR1) 的 MSC 可以归巢至肿瘤的假设。随后，我们将用 90Y（高能 β 发射体）标记 AABD 以诱导局部选择性辐射。因此，我们提出了一种新颖的体内治疗诊断方法。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；我们开发了一种细胞膜表达的抗体片段，称为 DAbR1，可以使用 86Y-AABD 通过正电子发射断层扫描 (PET) 进行检测。 AABD也可以用90Y标记用于放射治疗。治疗诊断将按如下方式使用：i)将表达DAbR1的MSC注射到荷瘤小鼠中。 ii) 86Y-AABD PET 成像将证实优化数量的 DAbR1-MSC 归巢至肿瘤。 iii) 仅在 PET 成像确认 DAbR1-MSC 最佳归巢至肿瘤以提供选择性肿瘤照射后，才会注射 90Y-AABD。拟议的研究人员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能力。在目标 1 中，我们将使用 86Y-AABD PET 分析表达 DAbR1 的 MSC 向小鼠肿瘤异种移植物的运输。我们将确定基因工程稳定表达 DAbR1 是否保留其正常增殖和分化。然后，我们将使用 86Y-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 DAbR1 的 MSC 在多个时间点的全身生物分布。在目标 2 中，我们将测试 90Y-AABD 在表达 DAbR1 的 MSC 肿瘤浸润后的治疗效果。该提案的最终目标是开发一种新型治疗诊断系统，用于使用放射性药物 90Y-AABD 进行高度特异性的癌症放射治疗。