Developing PARP-1 PET with companion tissue assay as a precision tool to guide PARPi therapy

Developing PARP-1 PET with companion tissue assay as a precision tool to guide PARPi therapy PROJECT SUMMARY When we give pharmaceuticals to patients with cancer, they deserve the best predictive measures we can employ to tell them whether the therapy has a significant likelihood of killing the tumor and extending their life. No one should have to suffer drug toxicity without benefit. If this proposal is successful, we will develop a noninvasive predictive biomarker of sensitivity to PARP inhibitors (PARPi) that could potentially be used for real- time dose modulation as well as patient selection. While our investigations will impact PARPi in any tumor type, we largely focus on breast cancer where PARPi are currently used in the setting of metastatic disease and the adjuvant setting. Here, the ability to predict response would also provide a critically needed biomarker to stratify patients for clinical trials testing neoadjuvant PARPi/chemotherapy combinations, especially in the triple- negative breast cancer population. BRCA1/2 and HRD testing indirectly select tumors that may be susceptible to PARPi, leveraging the concept of synthetic lethality, but do not directly measure drug-target density. The development of imaging-tissue markers for PARPi binding and PARP-1 expression is innovative in the context that currently used companion diagnostics for PARPi use genomic assays. Preliminary data in breast and ovarian cancer show that assay of the target (PARP-1), binding by PARPi, and measures of drug-target engagement provide complementary information that appears to add predictive value. In this proposal, we will develop a correlative tissue assay to a promising PARP- 1 radiotracer, using imaging, immunohistochemistry, and in vitro radioligand binding assay (Aim 1), test the assay for predictive value in historical clinical trial sets from patients who received PARPi with known clinical outcomes (Aim 2), and directly evaluate the hypothesis that tracer uptake predicts response in animal models of disease (Aim 3). The validated imaging agent and tissue companion diagnostic would have planned clinical use similar to fluoroestradiol imaging/estrogen receptor assessment. Clinicians could avoid futile therapy in cases where the target is not expressed and also potentially identify additional patients who would benefit from PARP-1 targeted therapy and combination strategies. Precision medicine is within our reach and needs to be employed for aggressive breast cancers. If successful, this research could lead to a new way to functionally characterize breast cancer, guide targeted therapy selection, and assess therapeutic response and resistance. The new imaging probe is immediately applicable to patients at our center and production has been standardized to facilitate multi-center use.