PET Imaging of Topoisomerase-II Expression in Breast Cancer

描述(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变细胞之间微小但有害的差异。在乳腺癌中，核酶Topo-11a(Topo-11o)的表达就是这样一个不同之处：正常细胞仔细调节其Topo-11a的表达水平，而癌细胞保持非常高的酶水平。然而，尽管靶向该酶的化疗药物占优势，Topo-11a的表达还没有被开发到诊断分子成像领域。我们建议设计、合成和开发一种新型的PET放射性示踪剂，用于乳腺癌拓扑异构酶水平的活体成像。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，这项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，从血液流动到营养消耗的过程都被用作示踪剂。靶基因Topo-11与乳腺癌之间的关系已经得到了充分的证明和深入的研究：仅在乳腺癌中，Topo-11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是放射性标记的缩氨基硫脲(Cu-TSC)。大量的研究表明，这些复合体可以特异性地靶向并强烈抑制Topo-11，使它们成为手头任务的完美选择。这项研究旨在系统地开发一种临床可翻译的铜(TSC)络合物，用于乳腺癌肿瘤Topo-11a表达水平的体内定量成像，将采用三阶段方法，从每个阶段选择最有希望的化合物进入下一个阶段。首先，我们将合成并表征一系列候选的铜-TSC络合物。接下来，我们将选择那些具有最有利特性的化合物，并将它们用于体外培养的乳腺癌细胞的检测，以进一步研究它们作为放射性示踪剂的潜力。最后，最有希望的化合物将使用小动物PET/CT成像，并在体内肿瘤模型中表达高和低水平的TOPO-11a。相关性：这项研究计划的最终目标是潜在的范式转变：开发一种正电子发射断层成像显像剂，使临床医生能够探索乳腺癌生物标记物Topo-11a在肿瘤中的水平。一种特异和灵敏的-铜-TSC TOPO-11LA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.