# The Role of RNA Editing in the DNMTi-induced interferon response in ovarian cancer

> **NIH NIH F31** · GEORGE WASHINGTON UNIVERSITY · 2022 · $9,883

## Abstract

High-grade serous ovarian cancer (OC) is a deadly disease that is often diagnosed at a late stage. Despite
significant research, the five-year survival rate for OC has remained unchanged for decades. Many OC tumors
develop chemoresistance, and only about 10% of OC patients respond to immunotherapy. Better OC
prognosis is associated with tumor-infiltrating CD8 T cells, so many research efforts focus on strategies to
activate the immune system against OC. DNA hypomethylating drugs have been shown to increase the
transcription of repetitive elements to induce an anti-viral innate immune response in OC cancer cell lines and
to reduce tumor burden and increase survival in mouse models through the same mechanism. RNA editing by
ADAR enzymes inhibits this anti-viral innate immune response. In preclinical mouse models, knockout of
ADAR1 in tumors increases the type I interferon response and reverses the immunosuppressive tumor
microenvironment (TME) to sensitize melanoma cells to immune therapy. We hypothesize that ADAR1
dampens the DNA methyltransferase inhibitor (DNMTi) immune response. Little is known about RNA editing of
different repetitive element species in cancers, and the role of RNA editing in the DNMTi-induced immune
response has not yet been explored. Studies in this application will test approaches to reduce tumor
immunosuppression and activate the immune system in OC, coupled with promising epigenetic therapies.
 In Aim 1, RNA editing of repetitive elements in human OC cell lines following DNMTi treatment will be
assessed through RNA editing analysis of RNA-sequencing data sets. In a second approach, RNA editing
reporter constructs will be stably transduced into OC cell lines and ADAR1 knockout cell lines will be
generated. Resulting RNA-editing levels, quantified by the luciferase reporter, will be measured in mock or
DNMTi-treated WT or reporter cell lines. Together, these studies will provide novel information about ADAR-
mediated regulation of RNA editing after DNMTi treatment and interferon signaling.
 Our preliminary data in mouse OC cells suggest that ADAR loss and type I interferon treatment induces
growth arrest and death. Adar1 knockout cells will be generated in the ID8 p53-/- syngeneic mouse OC cell line.
C57BL/6J mice will be injected with these syngeneic Adar1 KO cells and mice will be treated with DNMTi and
anti-PD1 or anti-CTLA-4. Tumor burden and survival will be assessed and infiltrating immune cells from the
tumor microenvironment (ascites) will be immunophenotyped to determine effects of epigenetic and immune
therapy. These studies may lead to development of drugs targeting ADAR1 or other proteins for cancer
immunotherapy. Knowledge gained from these studies is not only pertinent to the improvement of OC
treatment but may also be broadly applied to the improvement of treatment for other cancer types as well.

## Key facts

- **NIH application ID:** 10437855
- **Project number:** 5F31CA254315-03
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Stephanie Gomez
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $9,883
- **Award type:** 5
- **Project period:** 2020-07-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437855

## Citation

> US National Institutes of Health, RePORTER application 10437855, The Role of RNA Editing in the DNMTi-induced interferon response in ovarian cancer (5F31CA254315-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10437855. Licensed CC0.

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