# Optimizing theranostic radiopharmaceutical therapy to combat resistance to PARP inhibition in advanced ovarian cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $636,515

## Abstract

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.

## Key facts

- **NIH application ID:** 10851717
- **Project number:** 5R01CA278882-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael David Farwell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $636,515
- **Award type:** 5
- **Project period:** 2023-05-31 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851717

## Citation

> US National Institutes of Health, RePORTER application 10851717, Optimizing theranostic radiopharmaceutical therapy to combat resistance to PARP inhibition in advanced ovarian cancer (5R01CA278882-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10851717. Licensed CC0.

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