# Signaling basis of senescence-associated secretory phenotype and its implications in epithelial ovarian cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $495,433

## Abstract

Project Summary
Cellular senescence is a tumor-suppressive cell growth arrest triggered by inducers such as stand-of-care
epithelial ovarian cancer (EOC) chemotherapeutic platinum, known as therapy-induced senescence.
However, senescent cells are viable and may promote therapy relapse and immune escape through the
secretion of factors such as cytokines, chemokines, and growth factors, termed the senescence-
associated secretory phenotype (SASP). Thus, it would be ideal to selectively eliminate the detrimental
SASP while maintaining the senescence-associated growth arrest. Developing novel therapeutic
strategies to overcome therapy resistance remains a major obstacle to overcome in combating EOC. Thus,
the overall goal of this proposal is to investigate the mechanism underlying the SASP and leverage these
newly gained mechanistic insights to develop senescence based combinatory EOC therapeutics. cGAS
promotes the SASP through recognizing cytoplasmic chromatin fragments (CCF) during senescence. Our
preliminary studies show that the protein Thioredoxin Reductase 1 (TXNRD1) is localized to CCF and
TXNRD1 inhibition impairs the localization of cGAS into CCF, the cGAS-STING pathway, and the SASP
during platinum-induced senescence in EOC. Notably, TXNRD1 inhibition does not affect senescence-
associated growth arrest. The objectives of this application are to investigate the signaling basis by which
TXNRD1 controls the SASP and to investigate a combination senescence based EOC therapeutic
strategy. Our central hypothesis is that TXNRD1 promotes therapy relapse and resistance through the
SASP by activating the cGAS-STING signaling pathway during therapy-induced senescence in EOC.
Accordingly, two specific aims are proposed: Aim 1 is to elucidate the molecular mechanism by which
TXNRD1 regulates the SASP during senescence, and Aim 2 will determine the role of TXNRD1 in EOC
therapy response. The proposed studies are highly novel because this is the first study to explore a
molecular switch that controls the SASP by regulating the cGAS-STING signaling pathway via CCF. Thus,
our studies are paradigm-shifting in their potential to elucidate the molecular basis of SASP regulation
during senescence. The research proposed is of high impact because it will lay the critical foundation for
ultimately developing urgently novel EOC therapeutic strategies through limiting SASP-associated therapy
relapse and resistance. Therefore, the current study will not only provide critical mechanistic insights into
SASP regulation during senescence but will also have far-reaching implications for the development of
senescence-based therapeutic strategies.

## Key facts

- **NIH application ID:** 10897891
- **Project number:** 5R01CA276569-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Rugang Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $495,433
- **Award type:** 5
- **Project period:** 2023-08-02 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10897891

## Citation

> US National Institutes of Health, RePORTER application 10897891, Signaling basis of senescence-associated secretory phenotype and its implications in epithelial ovarian cancer (5R01CA276569-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10897891. Licensed CC0.

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