# Discovery of compounds and genes that regulate cancer's epigenome, using combinatorial screening in a nanodrop-microwell platform

> **NIH NIH F32** · BROAD INSTITUTE, INC. · 2020 · $29,860

## Abstract

Project Summary
Cancer relapse and the emergence of chemotherapy resistance are driven by epigenetic and transcriptional
profiles that repress tumor suppressor genes (TSGs). Small molecules that alter the epigenome to stimulate re-
expression of TSGs can re-sensitize tumors to chemotherapy; however, current drugs that target epigenetic
processes fail due to off-target effects (toxicity) or due to compensation from other epigenetic players
(resistance). Combination therapies target multiple nodes in an epigenetic network to reduce toxicity while
avoiding resistance, but exploring vast combinatorial space to identify such therapies is prohibitive using current
technologies. The overarching goal of this proposal is to unravel the interconnected networks that govern TSG
expression and identify small molecules that induce re-expression of TSGs using novel combinatorial platforms.
The approaches and technologies proposed may be applied to many cancers and TSGs; the expression of the
TSG CDKN2A in acute lymphoblastic leukemia (ALL) will be the focus of this work, as 20% of ALL cases result
in relapse, leading to grim prognoses, and CDKN2A is frequently repressed in relapsed ALL. To identify small
molecule combinations that may induce re-expression of CDKN2A in relapsed ALL, a proven combinatorial drug
screening platform developed in the Blainey Lab will be employed to screen the Broad Institute Drug Repurposing
Library for compounds that synergize with FDA-approved chemotherapies and epigenetic modifiers to induce
CDKN2A:GFP expression in an ALL cell line (Aim 1). In parallel, the protein networks that govern CDKN2A
expression in ALL will be identified by using high-throughput, barcoded, single-cell RNA sequencing (Seq-Well)
to screen a combinatorial CRISPR-Cas9 knockout library for CDKN2A expression (Aim 2). Finally, to look for
chemogenetic perturbations that cause re-expression of any TSG in ALL, a novel platform for high-throughput
RNA-sequencing of combinatorial chemogenetic libraries will be developed and used to sequence the
transcriptional outputs of all combinations of known epigenome-modifying drugs with the knockdown of each
annotated epigenomic regulator expressed in leukemia cells, including any identified in Aims 1 and 2. Validated
combinations of small molecules and genes from Aims 1-3 will constitute a new collection of lead compounds
and gene targets for the development of therapies that may extend the life-span and health-span of patients with
relapsed ALL.
The proposed research will be conducted in the Blainey Lab at the Broad Institute of MIT and Harvard, world-
leaders in the development of technologies that drive medical discovery. The results of this work will be presented
at national and international conferences and published in peer-reviewed journals as appropriate; all data will be
made available through public databases.

## Key facts

- **NIH application ID:** 9852879
- **Project number:** 5F32CA236425-02
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Cheri Marie Ackerman
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $29,860
- **Award type:** 5
- **Project period:** 2018-12-20 → 2020-06-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9852879

## Citation

> US National Institutes of Health, RePORTER application 9852879, Discovery of compounds and genes that regulate cancer's epigenome, using combinatorial screening in a nanodrop-microwell platform (5F32CA236425-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9852879. Licensed CC0.

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