# Radiobioeffect Modeling of αRPT

> **NIH NIH P01** · JOHNS HOPKINS UNIVERSITY · 2024 · $423,590

## Abstract

If absorbed dose is to be used in treatment-planning based α-particle emitter radiopharmaceutical therapy
(αRPT), the impact of DNA double-strand break (DSB) repair status- the process most likely to affect response
- must be considered in order to reliably predict toxicity and efficacy. Projects 1 through 3 have focused on
estimating tissue absorbed doses for αRPT. In project 4, we take these absorbed dose estimates and examine
whether clinically implementable methods for evaluating DNA DSB repair (DSBR) status will improve the
absorbed dose vs response relationship for patients undergoing αRPT. Our overall hypothesis is that tissue
absorbed dose will better predict αRPT response when adjusted by quantitative measures of DNA DSB repair
pathway functionality. To test this hypothesis, we introduce a novel approach to assessing repair pathway
functionality and couple it with preclinical and clinical scenarios that will allow us to rigorously evaluate the impact
of accounting for DSBR functionality in relating absorbed dose to response. We will use prostate cancer (PCa)
as a model system for the proposed studies. Prostate cancer patients are already treated with 223RaCl2 (Xofigo),
an FDA approved, αRPT. There is also evidence that the efficacy of this treatment is impacted by somatic and/or
germline deficiencies in DNA DSB repair. Accordingly, the proposed studies, will test our hypothesis in a context
that is immediately clinically relevant.
Aim 1: Using PCa cell lines and their repair deficient isogenic variants, relate absorbed dose (D) to DNA DSB
damage and repair, in vitro, in the context of BRCA2-/- and ATM-/- -related DNA DSB repair deficiencies; since
response is impacted by cell-cell interactions, perform these studies in (a) monolayer and (b) spheroid culture.
Aim 2: Collect dose- vs DSBR data, in vivo, analogous to that collected in Aim 1. Perform these studies in (a)
mice bearing xenografts of the cell lines and their isogenic variants used in Aim 1 and (b) extend the normal
organ studies of (a) using porcine marrow and kidney tissues from the dose vs toxicity studies of Aim 3 in Project
3. (c) In PCa patients treated with 223Ra, use normal tissue and tumor D estimates, with estimates of DSBR
functionality to assess the impact of DSBR deficiencies on D vs tumor and normal tissue response. DSBR
deficiencies will be assessed using DNA DSB repair (DDR) pathway mutation status obtained from liquid
biopsies.
Aim 3: Develop a mathematical model that may be used to optimize the selection and dosing schedule of DSBR
inhibitors (DSBRi) and identify patients whose genomic/transcriptomic profile and dosimetry would make them
likely high or low responders to αRPT±DSBRi therapy.
By coupling αRPT dosimetry with the DSBR functionality, the work proposed in this project completes the
transition depicted in figure 1 of the overview while also providing and validating a novel technique that can be
applied to investigating the role of DSBR inhibitors in αR...

## Key facts

- **NIH application ID:** 10931454
- **Project number:** 5P01CA272222-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** George Sgouros
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,590
- **Award type:** 5
- **Project period:** 2023-09-19 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931454

## Citation

> US National Institutes of Health, RePORTER application 10931454, Radiobioeffect Modeling of αRPT (5P01CA272222-02). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10931454. Licensed CC0.

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