One predominant subcellular response associated with both radiation therapy and the most common chemotherapeutic agents applied to cancers is severe DNA damage. This severe DNA damage is sensed by the enzyme Poly (ADP ribose) polymerase-1 (PARP-1), the activity of which becomes significantly elevated in cancer upon positive response to chemo and radiation therapy. In addition, it has been shown that some cancers have increased PARP-1 basal activity levels that may be responsible for a portion of the resistance of these cancers to certain conventional chemotherapeutic agents. Therefore, PARP-1 sensitive probes could have two-fold utility: (1) a criterion for cancer therapy individualization, and (2) a biochemical marker of early therapeutic response. By providing both pieces of information, a molecular imaging probe that responds to the activity of PARP-1 could allow a clinician to personalize cancer therapy. Thus, PARP-1 represents a subcellular marker for therapy-induced DNA damage whose activity can be directly correlated with therapeutic effect. Current probes for PARP-1 simply bind to the enzyme in both the active and inactive state, reporting on the amount of PARP-1 in a cell, but not the activity. However, it is the active fraction of total PARP-1 protein that correlates with the extent of DNA damage and the positive response of these cells to therapy, not the total PARP-1 protein levels. This research proposes to develop a novel PARP-1 activatable PET tracer for in vivo imaging of PARP- 1 activity, and to validate its application for imaging therapy response in a mouse model of cancer chemotherapy. There are two Aims: 1) Synthesize the PARP-1 activatable PET tracer, and assess its capacity to act as substrate, the stability of the formed polymers, and the effects of chemotherapy on PARP-1 activity in cell culture; 2) Validate the activatable PET tracer in animal models of cancer chemotherapy. Our novel probe would uniquely be capable of reporting the level off PARP-1 activity not protein, which should be more accurate at reporting a positive response to applied therapy than current methods involving serial tumor size measurements. Given the importance of monitoring tumor treatment response, the common use of PET for cancer imaging, and the unique potential of PARP-1 as a marker for personalizing therapy, this PARP-1 activatable PET tracer will significantly impact on our understanding of basal PARP-1 activity in vivo, and provide previously unattainable information regarding the real-time changes in PARP-1 activity during positive response to applied cancer therapy from which personalized therapy can be realized.
The proposed research aims to develop positron emission tomography (PET) imaging probe for non- invasive imaging of an important enzyme target PARP-1. The research is potentially clinical translatable for the individualization of cancer therapy, and the analysis of the tumor at the individual patient level with molecular imaging.