# The role of SERPINB3 in cervical cancer therapeutic resistance

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $605,457

## Abstract

PROJECT SUMMARY
High SERPINB3 is a biomarker of radioresistance, and a potential therapeutic target for cervical cancer. Our
recent work demonstrated that CRISPR-Cas9 knock out of SERPINB3, an inhibitor of lysosomal proteases,
sensitized cervical tumor cells to radiation therapy (RT)-induced cell death. In vivo targeting of SERPINB3 with
siRNA not only altered the tumor microenvironment, but significantly sensitized SERPINB3-high tumor models
to RT. Importantly, we established that tumor cells died via lysoptosis, a newly described and evolutionarily
conserved mode of cell death that is dependent upon lysosomal membrane permeabilization (LMP) and leakage
of potent proteases into the cytoplasm. SERPINB3-KO tumor cells underwent widespread lysoptosis when
treated with a variety of cytotoxic agents and chemotherapies. This suggests that loss of SERPINB3 exposed
lysoptosis as a default cell death mechanism in these cells. The molecular features of tumor cells that are
susceptible to RT-induced LMP and lysoptosis are unknown. Validation that lysoptosis leads directly to tumor
control is required. Additionally, the mechanism through which RT induces LMP is unknown. New unpublished
data suggest that SERPINB3-high tumors have a distinct molecular signature characterized by enrichment of
lysosome-related pathways. In these cells, LMP occurs soon after treatment with clinically relevant doses of RT,
while lysosomal rupture occurs days later just prior to cell death. Finally, we have identified candidate small
molecules that bind specifically to SERPINB3. The long-term goal of this work is to define new treatment
approaches for radioresistant SERPINB3-high tumors. This proposal tests the hypothesis that targeting
SERPINB3 in SERPINB3-high tumor cells renders them susceptible to RT-induced lysoptosis, and that LMP is
the initiating event that results from unrepaired lysosomal damage. Three aims are proposed to directly address
this hypothesis: Aim 1: Determine the predominant cell death mechanism induced by RT in SERPINB3-high
tumors; Aim 2: Determine the mechanism of therapy-induced LMP leading to lysoptosis; Aim 3: Identify
SERPINB3-targeting strategies that specifically sensitize tumor cells and not normal cells to RT. To accomplish
these aims, we propose to use ex vivo organelle-based approaches, step-wise in vitro and in vivo analysis of
cell death mechanisms leading to tumor control, and an innovative pre-clinical brachytherapy system that we
have developed to mimic treatment delivered in the clinic. Success of this proposal will confirm that SERPINB3
is a predictive biomarker for lysoptosis-inducing CRT strategies, generate new knowledge of the critical events
leading to RT-induced LMP and cell death, and provide innovative therapeutic strategies to target SERPINB3
and improve survival for patients with cervical cancer using a personalized treatment approach.

## Key facts

- **NIH application ID:** 10881578
- **Project number:** 1R01CA279293-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** STEPHANIE MARKOVINA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $605,457
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881578

## Citation

> US National Institutes of Health, RePORTER application 10881578, The role of SERPINB3 in cervical cancer therapeutic resistance (1R01CA279293-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10881578. Licensed CC0.

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