# Mechanisms and Therapy of Radiation Resistance in Breast Cancer

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $512,582

## Abstract

Summary: The goal of this revised proposal is to develop a novel therapeutic approach for overcoming
resistance to radiation therapy in triple negative breast cancer (TNBC) and to investigate the mechanism
involved. There is an urgent unmet need to develop strategies to overcome resistance so that the response of
TNBC patients to radiation therapy can be improved. This proposal is based on the hypothesis that vascular
endothelial growth factor (VEGF) signaling through neuropilin-2 (NRP2) in a population of tumor cells present in
TNBC contributes significantly to radiation resistance, and that inhibition of VEGF/NRP2 provides a novel
therapeutic approach for overcoming resistance. The feasibility of this approach is strengthened considerably
by the availability of a mAb that blocks the binding of VEGF to NRP2 specifically and that is available for clinical
use. The approach used benefits from the availability of a large collection of well-characterized organoids
derived from breast cancer patients and patient-derived xenograft (PDX) models of TNBC. The first aim will
investigate the mechanism by which VEGF/NRP2 signaling promotes radiation resistance based on the
observation that VEGF/NRP2 signaling promotes the transcription of nitric oxide synthase 2 (NOS2) and
increases the level of nitric oxide (NO). Based on this finding, the hypothesis will be investigated that
VEGF/NRP2 signaling sustains the S-nitrosylation of key proteins that contribute to radiation resistance,
including nuclear factor E2-related factor 2 (Nrf2), an
antioxidant transcription factor. The second aim will test
the hypothesis that targeted inhibition of the interaction of VEGF with NRP2 increases the radiosensitivity of
TNBC to a level that is clinically significant by a mechanism dependent on NOS2 inhibition. This goal will be
accomplished by assessing the response of a large panel of TNBC organoids of different subtypes that exhibit
inter-tumor heterogeneity to radiation and anti-NRP2 therapy using the function blocking mAb. RNA-seq will be
performed to identify potential biomarkers of resistant populations and this information will be used to identify
small molecule therapeutics that can be used to target those populations and improve the clinical viability of
aNRP2 treatment in combination with radiation.
This aim will also investigate the impact of this approach in vivo
using syngeneic and metastatic PDX models of TNBC. Overall, the work proposed in this proposal could
significantly improve the therapy of TNBC by selecting those patients who could benefit from anti-NRP2-
enhanced radiotherapy and, consequently, reduce the morbidity and mortality associated with TNBC.

## Key facts

- **NIH application ID:** 10980805
- **Project number:** 1R01CA285607-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Arthur M Mercurio
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $512,582
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980805

## Citation

> US National Institutes of Health, RePORTER application 10980805, Mechanisms and Therapy of Radiation Resistance in Breast Cancer (1R01CA285607-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10980805. Licensed CC0.

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