PET Imaging of Topoisomerase-II Expression in Breast Cancer

乳腺癌拓扑异构酶 II 表达的 PET 成像

• 批准号: 7803275
• 负责人: Brian Matthew Zeglis
• 金额: $ 4.52万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-27 至 2012-09-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803275
• 关键词: Acute; Animals; Autoradiography; Biodistribution; Biological; Biological Assay; Biological Markers; Blood flow; Breast Cancer Cell; Cancerous; Cells; Cessation of life; Chemicals; Chemotherapy-Oncologic Procedure; Complex; Consumption; Copper; Development; Diagnostic; Disease; Disease Progression; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Enzymes; Goals; Hand; Image; Immunohistochemistry; In Vitro; Lead; Ligands; Lip structure; Measurement; Modeling; Normal Cell; Nuclear; Nutrient; Oxidation-Reduction; Patients; Phase; Positron-Emission Tomography; Process; Property; Radioactive; Radiolabeled; Research; Role; Series; Small Interfering RNA; Staging; Techniques; Thiosemicarbazones; Topoisomerase; Topoisomerase II; Tracer; Translations; Western Blotting; analog; base; chemotherapeutic agent; chemotherapy; design; gel electrophoresis; imaging probe; in vitro Assay; in vivo; lipophilicity; malignant breast neoplasm; molecular imaging; novel; oncology; radiochemical; radiotracer; research study; response; tool; trait; treatment strategy; tumor; uptake

DESCRIPTION (provided by applicant): The molecular imaging and chemotherapy of cancer often depend upon the minute yet deleterious differences between normal cells and their cancerous counterparts. In breast cancer, the expression of the nuclear enzyme topoisomerase-lla (Topo-llo) is one such difference: normal cells carefully regulate their Topo-lla expression levels, while cancerous cells maintain very high levels of the enzyme. Yet despite the preponderance of chemotherapeutic agents that target the enzyme, Topo-lla expression has not yet been exploited in the realm of diagnostic molecular imaging. We propose the design, synthesis, and development of a novel PET radiotracer for the in vivo imaging of topoisomerase levels in breast cancer. All molecular imaging strategies can be broken down into three parts: technique, target, and tracer. In this case, the technique will be positron emission tomography (PET). Over the past 25 years, PET radiotracers have made a tremendous impact in oncology, with agents employed as tracers for processes ranging from blood flow to nutrient consumption. The relationship between the target, Topo-ll, and breast cancer is well documented and profound: in breast cancer alone, Topo-ll levels have been correlated with disease progression, response to chemotherapy, and disease-related death. Finally, the tracers in this study will be radiolabeled copper-thiosemicarbazones (Cu-TSC). An extensive body of research have shown that these complexes specifically target and strongly inhibit Topo-ll, making them a perfect choice for the task at hand. This study has been designed to systematically develop a clinically translatable Cu-(TSC) complex for the quantitative in vivo imaging of Topo-lla expression levels in breast cancer tumors, A three-stage approach will be employed, with the most promising compounds from each phase advancing to the next. First, we will synthesize and characterize a series of candidate Cu-TSC complexes. We will next select those compounds with the most advantageous traits and employ them in in vitro assays with cultured breast cancer cells to further investigate their potential as radiotracers. Finally, the most promising compounds will be screened using small animal PET/CT imaging with in vivo tumor models expressing high and low levels of Topo-lla. RELEVANCE: The ultimate goal of this research plan is potentially paradigm-shifting: the development for translation of a positron emission tomography imaging agent that would allow clinicians to explore the levels of the breast cancer biomarker Topo-lla in tumors. Not only would a specific and sensitive 64-Cu-TSC Topo- lla imaging probe have the potential to be a valuable diagnostic tool, it could concomitantly provide a wealth of information that would allow doctors to derive patient-specific treatment strategies.

描述（由申请人提供）：癌症的分子成像和化疗通常取决于正常细胞与其癌变细胞之间微小但有害的差异。在乳腺癌中，核酶拓扑异构酶-IIa (Topo-llo) 的表达就是这样一种差异：正常细胞仔细调节其拓扑异构酶-IIa 表达水平，而癌细胞则维持非常高水平的该酶。然而，尽管靶向该酶的化疗剂占优势，但 Topo-lla 表达尚未在诊断分子成像领域得到利用。我们建议设计、合成和开发一种新型 PET 放射性示踪剂，用于乳腺癌拓扑异构酶水平的体内成像。 所有分子成像策略都可以分为三个部分：技术、目标和示踪剂。在这种情况下，该技术将是正电子发射断层扫描（PET）。在过去的 25 年里，PET 放射性示踪剂对肿瘤学产生了巨大影响，其试剂被用作从血流到营养消耗等过程的示踪剂。靶标 Topo-II 与乳腺癌之间的关系已有充分记录且意义深远：仅在乳腺癌中，Topo-II 水平就与疾病进展、化疗反应和疾病相关死亡相关。最后，本研究中的示踪剂将是放射性标记的铜缩氨基硫脲（Cu-TSC）。大量研究表明，这些复合物专门针对并强烈抑制 Topo-ll，使其成为当前任务的完美选择。 本研究旨在系统地开发一种临床可翻译的 Cu-(TSC) 复合物，用于乳腺癌肿瘤中 Topo-lla 表达水平的定量体内成像。将采用三阶段方法，从每个阶段中选择最有前途的化合物阶段推进到下一个阶段。首先，我们将合成并表征一系列候选 Cu-TSC 配合物。接下来，我们将选择那些具有最有利特性的化合物，并将它们用于培养的乳腺癌细胞的体外测定中，以进一步研究它们作为放射性示踪剂的潜力。最后，将使用小动物 PET/CT 成像以及表达高水平和低水平 Topo-lla 的体内肿瘤模型来筛选最有前途的化合物。 相关性：该研究计划的最终目标可能是范式转变：开发正电子发射断层扫描成像剂的转化，使临床医生能够探索肿瘤中乳腺癌生物标志物 Topo-lla 的水平。特异且灵敏的 64-Cu-TSC Topolla 成像探头不仅有可能成为有价值的诊断工具，而且还可以同时提供丰富的信息，使医生能够制定针对患者的治疗策略。