# Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $425,312

## Abstract

Altered cellular metabolism has been widely recognized as an emerging hallmark of cancer. Although
recent advances in cancer metabolism research have begun to elucidate how metabolic changes support
cancer cell growth and survival, alterations in fatty acid (FA) metabolism in cancer cells have received less
attention. Increasing evidence has suggested that increased FA biosynthesis is needed not only to
accommodate high rates of proliferation by providing building blocks for membrane synthesis, but also to
enhance the ability of cancer cells to defend against oxidative stress- or chemotherapy-induced cell death by
changing membrane lipid composition. Studies from our laboratories and others have demonstrated that FA
synthase (FASN), a key enzyme of de novo lipid biosynthesis, is significantly upregulated in colorectal cancer
(CRC). Our in vivo studies demonstrate that RNAi-mediated inhibition of FASN markedly reduces lung and
hepatic CRC metastases and inhibits tumor angiogenesis. Collectively, our studies indicate FASN may serve
as a potential target for novel therapeutic agents. Recently, several orally-available, reversible, potent and
selective FASN small molecule inhibitors have been developed by our collaborator 3-V Biosciences. These
agents have excellent pharmaceutical profiles and achieve antitumor effects at tolerated doses in a broad
range of tumors including non-small cell lung cancer, ovarian and triple negative breast cancers. The
translational goal of our project is to define the metabolic adaptations that occur in colon cancer and to
conduct a clinical trial to evaluate the effect of FASN inhibitor, TVB-2640, on modulating cellular metabolism
and proliferation in colon cancer patients. The central hypothesis for our proposal is that upregulation of
FASN expression and activity occurs in a subset of colon cancer patients; therefore, these individuals would
benefit from a therapeutic approach that includes targeted inhibition of de novo lipogenesis. The following
Specific Aims are proposed: 1) to determine the effect of altered FASN expression on metabolic reprograming
in colon cancer; 2) to delineate the anti-proliferative effect of FASN inhibition using patient-derived xenograft
(PDX) models of colon cancer; and 3) to perform a pilot clinical trial in collaboration with 3-V Biosciences to
assess pharmacodynamic effects on metabolic endpoints following short-term treatment with a novel FASN
inhibitor (TVB-2640) prior to colon resection. Our highly collaborative group has the requisite expertise,
innovative model systems, state-of-the-art technology and novel inhibitors to make rapid progress that will
significantly advance our understanding of the FASN-mediated metabolic alterations of colon cancers and
potentially provide novel treatment strategies based on a more focused and personalized approach.

## Key facts

- **NIH application ID:** 10227741
- **Project number:** 5R01CA208343-05
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Bernard Mark Evers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $425,312
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227741

## Citation

> US National Institutes of Health, RePORTER application 10227741, Altered Lipid Metabolism as a Novel Target for Colon Cancer Treatment (5R01CA208343-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10227741. Licensed CC0.

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