# Effect of DNA repeat silencing on efficacy of ATRi in prostate cancer treatment

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $440,628

## Abstract

PROJECT SUMMARY
 Inhibition of the DNA replication checkpoint regulator ATR is a new and promising cancer treatment. ATR
inhibitors (ATRi) function as cancer treatments by causing double-stranded breaks (DSBs) at sites of problematic
DNA replication. Indeed, we have recently demonstrated that structure-forming repetitive DNA sequences
strongly influence on ATRi-driven breakage. However, our recent preliminary studies indicate that abnormal DNA
structure formation is not the sole determinant of vulnerability at these sites. We have now shown that ATRi-
driven breakage at inverted retroelement repeats is strongly stimulated by treatments that promote their
transcription. Moreover, because the transcription of retroelements is silenced at most genomic locations, their
derepression substantially increases breakage caused by ATRi.
 We hypothesize that cancer-associated alterations and silencing inhibitors that foster the transcription of
inverted retroelements will increase sensitivity to ATRi treatment. Importantly, advanced prostate cancer, most
notably castration-resistant prostate cancer (CRPC), exhibits many features expected to cause increased
transcription of inverted retroelements. These alterations include the hypomethylation of retroelements, the loss
of RB1 and p53-mediated repeat silencing, and the abnormal processing of RNA-DNA hybrids due to RNASEH2
deficiency. Herein, we propose to determine how each of these prostate cancer-associated changes affect the
localization and number of DNA breaks induced by ATRi. Furthermore, we will explore the molecular mechanism
by which inverted retroelement transcription increases ATRi-driven breakage at select sites and determine if
further inhibition of retroelement silencing by clinically approved drugs synergizes with ATRi to suppress the
growth of tumors in mouse models of CRPC. Finally, we will determine if this combination treatment is more
effective in the context of prostate cancer-associated mutation of ATM, BRCA2 and RB1. Collectively, these
studies will characterize new mechanisms by which cancer cells are sensitized to ATRi as well as identify novel
combination treatments for CRPC.

## Key facts

- **NIH application ID:** 10819526
- **Project number:** 5R01CA266645-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Eric J Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $440,628
- **Award type:** 5
- **Project period:** 2023-04-03 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819526

## Citation

> US National Institutes of Health, RePORTER application 10819526, Effect of DNA repeat silencing on efficacy of ATRi in prostate cancer treatment (5R01CA266645-02). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10819526. Licensed CC0.

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