# Targeting cancer metabolism as a novel synthetic lethality strategy for BRCA deficient breast cancers

> **NIH NIH F32** · UNIVERSITY OF CHICAGO · 2020 · $71,946

## Abstract

PROJECT SUMMARY
 This fellowship is directed at training the PI as a translational scientist and preparing
them to address major challenges in cancer treatment and health disparities. With the advanced
training proposed here, the PI will be poised to pursue an independent position leading a
research group focused on the interaction between cancer metabolism and genomic instability.
 Women who inherit the BRCA1 or BRCA2 mutation are at an increased risk of
developing breast and ovarian cancer. These cancers are a particular challenge in minority
populations where genetic testing, early diagnosis, and access to treatment are each
challenges. The BRCA1 and 2 gene products are required for normal levels of repair of DNA
double strand breaks (DSBs) by homologous recombination (HR), providing a rationale for the
"synthetic lethality" strategy of blocking other forms of DSB repair to sensitize BRCA deficient
cancer cells to endogenous DNA damage. Drugging DSB repair regulators such as PARP has
provided proof-of-principle, but most BRCA deficient patients fail to benefit from therapy.
 The Kron lab has shown that the Warburg effect impacts DSB repair by driving the
hexosamine biosynthetic pathway (HBP), leading to high intracellular protein O-GlcNAcylation
by O-GlcNAc transferase (OGT). Importantly, BRCA deficient cells display differential sensitivity
to OGT inhibition, displaying radiosensitivity and defects in DSB repair. This identifies a novel
strategy for synthetic lethal targeting in BRCA deficient breast cancer. In turn, high O-
GlcNAcylation can suppress the effects of PARP deficiency, suggesting that activation of OGT
may be a source of intrinsic resistance to PARP inhibitors.
 Here, we hope to confirm that targeting O-GlcNAcylation modulates cell survival in
BRCA deficient breast cancer cell lines both in vitro and in xenograft mouse models. Similarly,
we will evaluate blocking O-GlcNAcylation to enhance sensitivity to PARP inhibition and drive
synthetic lethality in BRCA deficient breast cancer. Finally, we will discover biomarkers that will
identify patients who may benefit from treatment with OGT inhibitors. Here, we will probe gene
expression signatures linked to activation of O-GlcNAcylation in BRCA deficient breast cance.
Taken together these studies may provide a rationale for targeting the HBP in BRCA deficient
breast cancer. Looking forward, gaining an understanding of how metabolism determines
cancer risk, progression and resistance may have major impacts in reducing disparities in
cancer incidence, treatment and outcomes.

## Key facts

- **NIH application ID:** 9992970
- **Project number:** 1F32CA250347-01
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Tamica N Collins
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $71,946
- **Award type:** 1
- **Project period:** 2020-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992970

## Citation

> US National Institutes of Health, RePORTER application 9992970, Targeting cancer metabolism as a novel synthetic lethality strategy for BRCA deficient breast cancers (1F32CA250347-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9992970. Licensed CC0.

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