PET Imaging of Topoisomerase-II Expression in Breast Cancer

描述（由申请人提供）：癌症的分子成像和化疗通常依赖于正常细胞和癌细胞之间微小但有害的差异。在乳腺癌中，核酶拓扑异构酶lla （Topo-llo）的表达就是这样一个区别：正常细胞小心地调节它们的Topo-lla表达水平，而癌细胞保持非常高的酶水平。然而，尽管靶向这种酶的化疗药物占据优势，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。所有分子成像策略可分为三个部分：技术、靶标和示踪剂。在这种情况下，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领域产生了巨大的影响，从血液流动到营养消耗等过程都采用了示踪剂。靶点、Topo-ll和乳腺癌之间的关系已被充分记录且意义深远：仅在乳腺癌中，Topo-ll水平与疾病进展、化疗反应和疾病相关死亡相关。最后，本研究中的示踪剂将被放射性标记铜硫代氨基脲（Cu-TSC）。广泛的研究表明，这些复合物特异性靶向并强烈抑制topo - 1，使它们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，每个阶段中最有希望的化合物将推进到下一个阶段。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征的化合物，并将其用于培养的乳腺癌细胞的体外试验，以进一步研究它们作为放射性示踪剂的潜力。最后，将通过小动物PET/CT成像和体内肿瘤模型来筛选最有希望的化合物，这些肿瘤模型表达高水平和低水平的Topo-lla。相关性：这项研究计划的最终目标是潜在的范式转换：开发一种正电子发射断层成像剂，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。特异且敏感的64-Cu-TSC Topo- lla成像探针不仅有可能成为一种有价值的诊断工具，而且还可以提供丰富的信息，使医生能够得出针对患者的治疗策略。

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.