# Investigating Mechanisms of Cancer Redox Homeostasis with Metabolic CRISPR-Based Screens

> **NIH NIH F30** · NORTHWESTERN UNIVERSITY · 2020 · $50,520

## Abstract

Project Summary and Abstract
The broad objectives of this NRSA Individual Fellowship are two-fold: 1) to facilitate the development of
essential skills that will allow the candidate to become an effective physician-scientist, and 2) to investigate
mechanisms of cancer redox homeostasis uncovered by CRISPR-based screens. The candidate and his
mentor have designed a specific training plan to achieve these objectives. The plan includes a rigorous
research component that lays the foundation for a successful career. This proposal concerns lung
adenocarcinoma and regulation of oxidative stress. Lung cancer remains the leading cause of cancer death
among both men and women. The recent success of metabolic drugs, such as complex I inhibitors, have
revitalized interest in targeting cancer metabolism. However, many of these drugs have unacceptable side
effects. A more thorough understanding of cancer metabolic reprogramming is necessary for the development
of effective and safer, metabolically targeted cancer therapies.
Recent studies have uncovered that the dietary consumption of cruciferous vegetables, such as broccoli, is
associated with a decreased risk of cancer. Their chemoprotective properties are attributed to isothiocyanates
such as phenethyl isothiocyanate (PEITC). Although it known that PEITC disrupts the delicate cancer redox
balance, the mechanism by which this occurs is unknown. The candidate has preliminary data utilizing a
metabolism focused CRISPR-based screen revealing KDM5C as required for PEITC-induced lung
adenocarcinoma cell death and SCD1 as synthetic lethal with PEITC. The focus of this proposal is to validate
these gene hits and examine the mechanisms by which KDM5C and SCD1 regulate the cellular antioxidant
response. The long-term goal of this proposal is to identify therapeutic metabolic targets that may lead to more
effective and safer therapies for patients with lung cancer.
In Specific Aim 1, the candidate will determine whether KDM5C is required for PEITC-induced lung
adenocarcinoma cell death by repressing antioxidant genes. Analysis of KDM5C regulation of histone
modifications and their downstream effects on gene expression will be used to determine the extent to which
KDM5C is a negative regulator of cellular antioxidant response. In Specific Aim 2, the candidate will determine
the molecular mechanism by which inhibition of SCD1 is synthetic lethal with PEITC to induce lung
adenocarcinoma cell death. Lipidomics will quantify the extent to which SCD1 regulates cellular lipid levels.
Measurements of ER and mitochondrial stress will provide insight into the mechanism by which SCD1 is
synthetic lethal with PEITC. The proposed studies will identify and causally validate previously unknown
mechanisms of cellular redox homeostasis in cancer and provide evidence to devise effective combinatorial
therapies to target this balance.

## Key facts

- **NIH application ID:** 9992446
- **Project number:** 1F30CA250236-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Karthik Vasan
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 1
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992446

## Citation

> US National Institutes of Health, RePORTER application 9992446, Investigating Mechanisms of Cancer Redox Homeostasis with Metabolic CRISPR-Based Screens (1F30CA250236-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9992446. Licensed CC0.

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