# PSMA ligand radiosensitizers to improve the therapeutic index of external beam radiotherapy for prostate cancer

> **NIH NIH R03** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $88,000

## Abstract

PROJECT SUMMARY/ABSTRACT:
Radiation therapy has a definitive role in curing high risk, very high risk, and even oligometastatic or low-
volume metastatic disease as phase III trials in these settings have demonstrated overall survival benefits.
However, radiation therapy also involves incidental radiation dose to rectum, small bowel and urethra, which
cause radiation dose-limiting toxicity. Locoregional control, particularly within pelvic lymph node regions where
currently possible radiation doses are non-curative, can be a limiting factor in overall prostate curability in these
settings. In this proposal, we seek to create state-of-the-art PSMA-targeting therapeutics, taking advantage of
this relatively prostate-specific surface antigen. We will create two molecules consisting of the PSMA ligand
linked to a lysosomal cleavable linker which is turn linked to radiation sensitizing small molecule inhibitors of
the DNA damaging response. One molecule will involve a potent inhibitor of ATM and the second will involve
an inhibitor of DNA-PK, two targets integral to radiation efficacy. In SA1 we will test these novel molecules with
in vitro assessments of inhibition of the ATM and DNA-PK kinases in PSMA expressing prostate cancer cell
lines compared to PSMA non-expressing cells. In SA2, we will test these molecules for in vivo efficacy in
prostate cancer xenografts and determine target engagement and preliminary normal tissue toxicity. The
overarching goal addressed by the proposed research project is to develop treatments that could improve
survival for men with lethal prostate cancer by improving locoregional control, which does impact overall
survival in these men. In addition, if these molecules successfully radiosensitize, it is also possible they will
allow for external beam radiation dose de-escalation and enable less normal tissue toxicity in order to improve
quality of life outcomes. Finally, in downstream work the molecules could be combined with Radium-223 to
systemically radiosensitize a therapy proven to extend survival. In this pilot grant, we will determine the initial
feasibility of this approach, laying the groundwork for further therapeutic development.

## Key facts

- **NIH application ID:** 10872550
- **Project number:** 1R03CA286680-01A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Daniel Higginson
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $88,000
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872550

## Citation

> US National Institutes of Health, RePORTER application 10872550, PSMA ligand radiosensitizers to improve the therapeutic index of external beam radiotherapy for prostate cancer (1R03CA286680-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10872550. Licensed CC0.

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