Molecular imaging of novel PARP inhibitor nanomedicine delivery

PROJECT SUMMARY The goal of this proposal is to develop novel PARP inhibitor nanomedicine and a companion PET biomarker for treatment of prostate cancer. Despite recent advances, metastatic castration resistant prostate cancer remains a lethal, incurable disease with poor outcomes. Recently, PARP inhibitors have demonstrated great promise in this disease in patients bearing enabling mutations. We have developed a novel nanomedicine, star-PEG-TLZ4, with a cleavable linker which enhances delivery of talazoparib, a PARP inhibitor, to tumors while reducing potential toxicity. We have also developed a cognate molecular imaging tool, [89Zr]DFO-star-PEG-TLZ3, which enables imaging of the delivery of this nanomedicine. In this proposal, we develop [89Zr]DFO-star-PEG-TLZ3 and star-PEG-TLZ4 as novel imaging agent and drug combination in prostate cancer. The central hypothesis of this proposal is that the star-PEG backbone will enable enhanced delivery of PARP inhibitors and the imaging agent to prostate cancer, both in animal models as well as in a pilot translational study. In order to test this hypothesis, we have assembled an experienced team of chemists, imaging scientists, physicists, and physicians to evaluate this method in preclinical models and to perform initial feasibility testing in men with metastatic prostate cancer. In specific aim 1, we test the biodistribution of [89Zr]DFO-star-PEG-TLZ3 in prostate cancer preclinical models including patient derived xenografts. In specific aim 2, we test if [89Zr]DFO- star-PEG-TLZ3 can serve as a companion biomarker of star-PEG-TLZ4 mediated talazoparib delivery, and test the efficacy of star-PEG-TLZ4 in prostate cancer models bearing enabling mutations. In specific aim 3, we perform a translational study in men with prostate cancer, to determine the feasibility of star-PEG mediated drug delivery and imaging in men with that disease. These experiments will help aid the development and implementation of star-PEG mediated PARPi delivery, thereby improving patient care for men with prostate cancer.