# Project 4:  The Role of Fatty Acid Synthase in Colorectal Cancer

> **NIH NIH P20** · UNIVERSITY OF KENTUCKY · 2020 · $306,129

## Abstract

PROJECT SUMMARY 
 Metastasis is the main cause of death from solid tumors including colorectal cancer (CRC). My long-term 
goal is to develop more selective therapeutic options to prevent or reduce the incidence of CRC metastasis by 
understanding how changes in de novo fatty acid synthesis contribute to metastatic disease. Fatty acid 
synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated and activated in CRC, 
and its activity is associated with poor prognosis, higher risk of disease recurrence, and death. I have identified 
FASN as a potential target for advanced stages of disease and showed that upregulation of this enzyme is a 
key mechanism supporting metastasis in CRC. However, the underlying mechanisms of regulation of 
metastasis by FASN are not understood. The current application proposes a comprehensive research plan to 
study novel mechanisms of regulation of growth, survival and metastasis by FASN in CRC. Our preliminary 
studies show that overexpression of FASN is associated with an increase in cellular respiration, including β- 
oxidation, inhibition of autophagy, and accumulation of lipid droplets. Therefore, in Aim 1, we will elucidate the 
role of FASN in reprogramming of metabolic pathways and lipid storage in order to maintain energy 
homeostasis and promote survival of cancer cells. Furthermore, our preliminary data suggest that the primary 
product of de novo fatty acid synthesis, palmitate, is selectively used for sphingolipid synthesis and 
overexpression of FASN increases the level of sphingosine-1-phosphate (S1P), a bioactive sphingolipid, 
known to enhance migration and invasion of cancer cells. Therefore, in Aim 2, we will test the hypothesis that 
FASN promotes metastasis via activation of sphingosine kinases and an increase in S1P signaling. Finally, in 
Aim 3, we will test the effect of FASN inhibitor on proliferation in CRC patient-derived xenografts (PDXs) as a 
monotherapy and in combination with an autophagy inhibitor and identify potential biomarkers associated with 
CRC responsiveness to FASN inhibition. 
 I will utilize biological samples from patients, human primary cells and PDX models, which are the most 
advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with 
state-of-the-art approaches, including Stable Isotope-Resolved Metabolomics (SIRM) to evaluate the effect of 
FASN overexpression on cancer metabolism. The differential expression of FASN in normal versus cancer 
cells makes de novo lipogenesis a desirable target for therapeutic intervention. I anticipate that the proposed 
work will identify a subset of CRC patients who would benefit from targeted FASN inhibition and further 
advance our understanding of the role of FASN in CRC that would potentially lead to the development of novel 
therapeutic strategies to treat this disease.

## Key facts

- **NIH application ID:** 9849297
- **Project number:** 5P20GM121327-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** YEKATERINA ZAYTSEVA
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,129
- **Award type:** 5
- **Project period:** 2020-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849297

## Citation

> US National Institutes of Health, RePORTER application 9849297, Project 4:  The Role of Fatty Acid Synthase in Colorectal Cancer (5P20GM121327-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9849297. Licensed CC0.

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