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.
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.
