[18F]-Labeled PARP-1 PET imaging of PSMA targeted alpha particle radiotherapy response.

The growing interest and clinical translation of alpha particle (α) therapies brings with it new challenges to assess target cell engagement and to monitor therapeutic effect. Noninvasive imaging has great potential to guide α-treatment and to harness the potential of these agents in the complex environment of disseminated disease. Poly(ADP) ribose polymerase 1 (PARP-1) is among the most abundantly expressed DNA repair enzymes with key roles in multiple repair pathways-such as those induced by irradiation. Here, we used a third-generation PARP1-specific radiotracer, [18F]-PARPZ, to delineate castrate resistant prostate cancer xenografts. Following treatment with the clinically applied [225Ac]-PSMA-617, positron emission tomography was performed and correlative autoradiography and histology acquired. [18F]-PARPZ was able to distinguish treated from control (saline) xenografts by increased uptake. Kinetic analysis of tracer accumulation also suggests that the localization of the agent to sites of increased PARP-1 expression is a consequence of DNA damage response. Together, these data support expanded investigation of [18F]-PARPZ to facilitate clinical translation in the ⍺-therapy space.

PSMA expression in the Hi-Myc model; extended utility of a representative model of prostate adenocarcinoma for biological insight and as a drug discovery tool.

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is highly overexpressed in primary and metastatic prostate cancer (PCa). This has led to the development of radiopharmaceuticals for targeted imaging and therapy under current clinical evaluation. Despite this progress, the exact biological role of the protein in prostate cancer development and progression has not been fully elucidated. This is in part because the human PSMA and mouse PSMA (mPSMA) have different patterns of anatomical expression which confound study in the most widely utilized model organisms. Most notably, mPSMA is not expressed in the healthy murine prostate. Here, we reveal that mPSMA is highly upregulated in the prostate adenocarcinoma of the spontaneous Hi-Myc mouse model, a highly accurate and well characterized mouse model of prostate cancer development. Antibody detection and molecular imaging tools are used to confirm that mPSMA is expressed from early prostatic intraepithelial neoplasia (PIN) through adenocarcinoma.