# Radiosensitizing the SUMO stress response intensifies single-dose radiotherapy tumor cure

## TL;DR

Combining an antiangiogenic drug with single-dose radiotherapy improves tumor cure by enhancing DNA damage and reducing repair.

## Contribution

The study demonstrates that sensitizing the SUMO stress response radiosensitizes tumors without harming normal tissues.

## Key findings

- DC101 radiosensitizes tumors by 4–8 Gy at all clinically relevant doses.
- The SUMO stress response inactivates DNA repair enzymes, enhancing tumor cure.
- Normal tissues are not sensitized by the treatment, reducing side effects.

## Abstract

Single-dose radiotherapy (SDRT) is a highly curative modality that may transform radiotherapy practice. Unfortunately, only ~50% of oligometastatic lesions are SDRT treatable due to adjacent radiosensitive normal organs at risk. Here, we address the extent to which an antiangiogenic drug, VEGFR2-antagonist DC101, radiosensitizes SDRT using murine MCA/129 fibrosarcomas and Lewis lung carcinomas, which display a dose range for SDRT lesional eradication virtually identical to that employed clinically (10–30 Gy). SDRT induces unique tumor cure, stimulating rapid endothelial acid sphingomyelinase (ASMase)/ceramide signaling that yields marked vasoconstriction and perfusion defects in tumor xenografts and human oligometastases. Ensuing tumor parenchymal oxidative damage initiates a SUMO stress response (SSR), which inactivates multiple homologous recombination repair enzymes, radiosensitizing all tumor types. While VEGF inhibits neo-angiogenic ASMase, optimal radiosensitization occurs only upon antiangiogenic drug delivery at ~1 hour preceding SDRT. Obeying these principles, we find DC101 radiosensitizes SSR, DNA double-strand break unrepair, and tumor cure by 4–8 Gy at all clinically relevant doses. Critically, DC101 fails to sensitize small intestinal endothelial injury or lethality from the gastrointestinal–acute radiation syndrome. Whereas normal tissues appear not to be under VEGF regulation nor sensitized by our approach, its application might render many currently intractable oligometastatic lesions susceptible to SDRT eradication.

Sensitizing the SUMO Stress Response markedly increases single dose radiotherapy-induced double strand break unrepair and tumor cure at all clinically-relevant doses in pre-clinical models