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学疗法通常取决于正常细胞与其癌性对应物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）的表达就是这样一个差异：正常细胞仔细调节其Topo-lla表达水平，而癌细胞保持非常高的酶水平。然而，尽管靶向该酶的化疗剂占优势，Topo-IIa表达尚未在诊断分子成像领域中被利用。我们提出了一种新的PET放射性示踪剂的设计，合成和开发的拓扑异构酶水平在乳腺癌的体内成像。 所有的分子成像策略可以分为三个部分：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放射性示踪剂在肿瘤学中产生了巨大的影响，从血流到营养消耗的过程中都使用了示踪剂。靶点Topo-II和乳腺癌之间的关系是有据可查的和深刻的：在单独的乳腺癌中，Topo-II水平与疾病进展、对化疗的反应和疾病相关的死亡相关。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，这些复合物特异性靶向并强烈抑制Topo-II，使其成为手头任务的完美选择。 本研究旨在系统地开发一种临床上可翻译的Cu-（TSC）复合物，用于乳腺癌肿瘤中Topo-IIa表达水平的定量体内成像。将采用三阶段方法，其中每个阶段的最有前途的化合物进入下一阶段。首先，我们将合成和表征一系列候选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，并将其用于培养的乳腺癌细胞的体外试验，以进一步研究其作为放射性示踪剂的潜力。最后，将使用小动物PET/CT成像，使用表达高和低水平Topo-lla的体内肿瘤模型来筛选最有希望的化合物。 相关性：这项研究计划的最终目标是潜在的范式转变：开发正电子发射断层扫描成像剂的翻译，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。特异性和灵敏性的64-Cu-TSC Topo-1 la成像探针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，使医生能够得出患者特异性的治疗策略。