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Description

Altered metabolism is recognized as a common hallmark of cancer. Dysregulation of glucose metabolism has been extensively studied; however, the role of fatty acid (FA) metabolism in tumorigenesis and disease progression, as well as treatment resistance, remains poorly understood. Following our initial discovery of FASN, a key enzyme of de novo lipid biosynthesis, as an important regulator or tumor progression in colorectal cancer (CRC), studies from our group and others have firmly established an oncogenic role of FASN in multiple tumor types. Increased fatty acid biosynthesis is needed not only to accommodate high rates of proliferation by providing building blocks for membrane synthesis, but also to enhance cancer cells’ ability to defend against oxidative stress- or chemotherapy-induced cell death by changing membrane lipid composition. Given the strong rationale for targeting FASN in cancer therapy, a new class of potent and selective small molecule inhibitors of FASN (TVBs) have been developed and characterized in pre-clinical and clinical investigations. Our group has conducted a double-blind, randomized, placebo-controlled window trial with TVB-2640 in patients with resectable colon and other cancers. Results from the interim analysis of this ongoing clinical investigation revealed that short-term oral TVB-2640 therapy demonstrates excellent on-target inhibition of de novo lipogenesis and manageable safety profile. However, our preclinical studies using CRC patient-derived xenografts (PDXs) showed that FASN inhibitors only modest reduce tumor growth despite a significant decrease in lipogenesis in vivo. Thus, targeting FASN alone is unlikely to be sufficient to eradicate cancer cells. In exciting new findings, we showed that FASN inhibition potentiates chemotherapy drug-induced DNA damage in colon cancer cells as a result of altered histone acetylation. In addition, we discovered that FASN inhibition promotes the activation of the cGAS/STING pathway and downstream type I interferon (IFN) response. The overall objective of this study is to identify novel mechanisms that can enhance the antitumor efficacy of FASN inhibitors in CRC. The central hypothesis driving this proposal is that a combination treatment strategy, which includes FASN inhibition, will prevent chemoresistance by blocking DNA damage response and potentiating the activation of innate immune signaling via epigenetic mechanisms. The following Specific Aims are proposed: 1) to define the molecular mechanisms by which FASN inhibition blocks DNA repair pathways; 2) to delineate the functional significance of FASN inhibition on modulating tumor immune microenvironment; and 3) to determine the synergistic effects of FASN inhibitor and chemotherapy agents in vivo. 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 potentially provide novel treatment options to improve patient outcome.
StatusActive
Effective start/end date3/1/242/28/29

Funding

  • National Cancer Institute: $402,968.00

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