# Hedgehog/Gli1-targeted therapies to overcome ovarian cancer chemoresistance and disease recurrence

> **NIH NIH R01** · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · 2020 · $563,747

## Abstract

Abstract
Ovarian cancer (OC) is deadly and incurable for patients that recur after primary cancer is treated with surgery
and platinum-based chemotherapy. Unfortunately, OC has a high rate of disease recurrence (70-80%) and
most recurrent tumors are chemoresistant. Currently, therapeutic options are quite limited for these patients,
and thus unlike with other cancers, the mortality in OC has not improved in decades. This dreadful situation
highlights a drastic need for new and improved therapeutics to eliminate and treat recurrent and
chemoresistant disease. In this context our studies identified increased Hedgehog (Hh)/GLI signaling in
chemoresistant OC cells and tumors, and GLI1 expression significantly correlated with upregulated FA-BRCA
and homologous recombination (HR) genes, cancer stem cell signaling and poor prognosis of OC patients. Our
preliminary data demonstrate that GLI1 regulates expression of DNA repair genes BRCA1, FANCD2 and
RAD51 in OC cells and tumors and its inhibition induces a state known as “BRCAness”, which is characterized
by inefficient repair of DNA double strand breaks (DSB). Additionally, Hh/GLI1 inhibition or downregulation
decreased cell survival and ability to form tumor spheroids (stem cell characteristic), and enabled synthetic
lethality with PARP inhibitors. In this proposal we aim to elucidate the molecular mechanisms by which
Hh/GLI1 regulates FA-BRCA and HR genes that promote oncogenic replication (Aim 1), and determine the
efficacy of Hh/GLI1 inhibitors in both BRCA-proficient and deficient OC cells in cell line and ovarian cancer
orthotopic mouse models (Aim 2). Towards the goal of identifying effective therapeutic combinations that work
synergistically and induce synthetic lethality, we will evaluate effective therapeutic combinations involving
Hh/GLI1 and PARP inhibitors. The most efficient drug combinations will be examined in a mouse orthotopic
and patient derived xenograft models of OC to evaluate their efficacy in combatting acquired chemoresistance
and OC disease progression (Aim 3). Chemotherapeutic drugs examined in this proposal are FDA approved or
currently undergoing clinical and preclinical evaluation (ex. vismodegib, sonidegib, GANT61, olaparib,
rucaparib, niraparib); thus, the effective drug combinations discovered can quickly be transitioned into clinical
trials and developed into treatments for OC patients.

## Key facts

- **NIH application ID:** 9868899
- **Project number:** 5R01CA219187-03
- **Recipient organization:** TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
- **Principal Investigator:** Komaraiah Palle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $563,747
- **Award type:** 5
- **Project period:** 2018-02-15 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868899

## Citation

> US National Institutes of Health, RePORTER application 9868899, Hedgehog/Gli1-targeted therapies to overcome ovarian cancer chemoresistance and disease recurrence (5R01CA219187-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868899. Licensed CC0.

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