# Identifying the Drivers and Targeting Chemo Resistance in Ovarian Cancer

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $411,369

## Abstract

PROJECT SUMMARY/ABSTRACT
Ovarian cancer is the most lethal gynecological malignancy. Although majority of the cancer cases are
initially sensitive to platinum-based chemotherapy, most patients eventually develop recurrence and
succumb to chemoresistant disease. Our lack of understanding of the key drivers that lead to the
resistant state poses a critical roadblock that impedes therapeutic progress in the field. The long-term
goal of our research is to understand the chromatin and transcriptional regulatory networks that allow
cells to adapt to new environmental or developmental cues. The overall objective of this study, which is
the next step toward attainment of our long-term goal, is to identify the major regulatory networks that
allow ovarian cancer cells to survive chemotherapy. This knowledge will identify improved and effective
therapeutics options.
 To achieve this, we started with epigenome mapping and transcriptome analysis of an in vitro
system in which we employed chemonaïve, chemoresistant, and resensitized isogenic cells. Integrative
analysis of expression profiles (RNA-Seq) and epigenomic features of promoter and enhancer
elements (H3K27ac ChIP-Seq), identified large number of typical enhancers and a subset of “super
enhancers” that are specifically activated in resistant cells. Notably, pharmacological disruption of super
enhancers by a small molecule epigenetic inhibitor confers cisplatin sensitivity to previously resistant
cells in vitro and inhibits in vivo tumor growth in a xenograft model of resistant cells. Super enhancers
tend to regulate the expression of master regulators of a given cellular state (1, 2). Among the top
target genes of the resistant specific super enhancers (RSSE) were multiple transcription factors,
whose depletion with CRISPR mediated knock significantly sensitized the resistant cells to
chemotherapy.
 These preliminary data led to the central hypothesis that aberrant transcriptional program in
chemoresistant cells is driven by a set of genes whose expression is regulated by distal enhancers that
can be pharmacologically targeted. This proposal will determine the therapeutic efficacy of enhancer
targeting to overcome chemoresistance (Aim 1), identify the in vivo dynamics of chemotherapy-induced
aberrant enhancer activation (Aim 2), and delineate the core TFs that drives the chemoresistance
process (Aim 3). The rationale is to identify and target the major drivers of chemoresistant cellular state
genetically, epigenetically, and pharmacologically. The results will allow us to better understand the
biology of chemoresistance, and enable development of new and innovative treatment approaches that
are applicable to other cancers.

## Key facts

- **NIH application ID:** 9868921
- **Project number:** 7R01CA211648-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mazhar Adli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $411,369
- **Award type:** 7
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868921

## Citation

> US National Institutes of Health, RePORTER application 9868921, Identifying the Drivers and Targeting Chemo Resistance in Ovarian Cancer (7R01CA211648-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868921. Licensed CC0.

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