Sunday, June 1, 2025
6/1/2025
Optimizing theranostic radiopharmaceutical therapy to combat resistance to PARP inhibition in advanced ovarian cancer - Project Summary (limited to 30 lines) Ovarian cancer is a devastating gynecologic malignancy with 13,770 estimated US deaths in 2021 with a 49.1% relative 5 year survival rate (SEER). Leveraging the considerable fraction of women with ovarian cancer who have germline or somatic homologous recombination deficiencies (HRD), poly (ADP-ribose) polymerase 1 inhibitors (PARPi) have become standard of care for ovarian cancer. Unfortunately, most patients treated with PARPi develop resistance. Interestingly, most PARPi resistant patients continue to express activated PARP-1 (the target of PARPi) in the nucleus. This finding has guided our alpha theranostic radiopharmaceutical approach to treating PARPi-resistant ovarian cancer to deliver cytotoxic alpha particles directly to the nucleus of cancer cells to create lethal, double stranded DNA breaks. Our platform is based on a small molecule similar to the approved PARPi, rucapararib, labeled with 18F for PET ([18F]fluorthanatrace, [18F]FTT) and 211At for alpha therapy ([211At]parthanatrace, [211At]PTT). Our overarching hypothesis is that [211At]PTT can overcome PARPi resistance with an acceptable therapeutic ratio and that the theranostic pair of [211At]PTT and [18F]FTT will allow accurate pre-treatment dosimetry to guide both efficacy and tolerability of therapy. Using mouse models of ovarian cancer, we plan to (1) measure the comparative dynamic biodistribution of the proposed theranostic pair, [18F]FTT and [211At]PTT to verify preliminary data supporting similar tumor uptake and tissue kinetics, (2) understand the dose-response relationship in tumor and organs at risk (both those expressing considerable PARP-1 and those with off target agent biodistribution); (3) carry out pre-clinical studies to assess toxicity and efficacy of the [211At]PTT /[18F]FTT theranostic approach with optimized dose fractionation. Our specific aims are as follows: SA1—Biodistribution and Pharmacokinetics: Test the comparative biodistribution of [18F]FTT and [211At]PTT in normal tissue and ovarian cancer. SA2—Dose-response relationship: Develop and validate on- and off-target normal organ dose limits and tumor dose-response relationship utilizing [18F]FTT PET/CT to predict dosimetry from [211At]PTT. SA3—Pre-clinical trials: Determine the optimal dosing scheme and estimate efficacy in patient derived ovarian cancer murine models. Successful completion of these aims will provide data needed for a first in human clinical trial of [18F]FTT -guided [211At]PTT therapy in women with advanced PARPi-resistant ovarian cancer and will provide insight into tumor factors mediating effective alpha particle therapy to guide patient selection in clinical trials and clinical practice.
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