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    Home > Research & Grants > Grants Program > Research Grants > Research Grants Awarded > Abstract
    Awarded Grants
    Antitumoral Efficacy of Novel Inhibitors of the Fatty Acid Synthase

    Scientific Abstract:
    Background. Fatty acid synthase (FAS) is an enzyme normally expressed in the liver, fatty tissue and proliferating endometrium, and abnormally expressed in some cancers, most notably breast cancer, where it is associated with an adverse prognosis. Cerulenin and C75, two FAS inhibitors, have anticancer activity, and we have shown that they enhance the efficacy of other cancer treatments. However, the chemical structure of these compounds has limited their therapeutic application. Furthermore, these molecules have significant adverse effects such as anorexia. Recently it has been described that epigallocatechin-gallate (EGCG), isolated from green tea, is a natural inhibitor of FAS, and is also a potent inhibitor of carcinogenesis. The antitumor activity of EGCG has been characterized, but studies suggest that EGCG is poorly absorbed and undergoes considerable biotransformation to other species. Therefore, it is worth to identify new EGCG derivatives with better absortion and retain the anticancer activity. Hypothesis. We hypothesize that the new molecules derived from EGCG have antitumoral activity and enhance the efficacy of current cancer treatments by inhibiting the FAS. Specific Aims. 1) To determine which of the EGCG derived compounds exhibit inhibitory capacity against FAS activity. 2) To determine which of the EGCG derived compounds inhibit cell proliferation of different breast cancer cell lines. 3) To determine if the EGCG derived compounds enhance the efficacy of Docetaxel and Trastuzumab. 4) To determine the molecular mechanisms of the compounds that showed higher inhibition of cell proliferation in our cell models. Study Design: Several breast carcinoma cell lines expressing different levels of FAS will be treated with EGCG derivatives and FAS enzimatic activity will be measured. To determine the antitumoral effect of the EGCG compounds we will measure cell proliferation using the MTT assay. To asses the molecular mechanisms underlying FAS inhibition we will measure erbB-2 and EGFR levels using ELISA. In addition, changes in downstream molecules of these receptors will be detected by immunoblot analysis and RT-PCR. Finally, the apoptotic effects of the EGCG derivatives will be measure by several techniques including TUNEL, among others. Potential Outcomes and Benefits This research will provide further evidence that FAS is an important anticancer target. Our research will identify which of the new compounds can be further used in novel clinical trials in breast cancer patients, etheir alone or in combination with other cancer treatments.

    Lay Abstract:
    Fatty acid synthase (FAS) is an enzyme abnormally expressed in some cancers, most notably breast cancer, where it is associated with an adverse prognosis. Recently it has been described that a compound isolated from green tea, is a natural inhibitor of FAS, and also inhibits tumor growth. However this compound is poorly absorbed which limits its efficacy and have significant adverse effects. Therefore, it is worth to identify new derivatives of this molecule with better absortion and the same or better anticancer activity. For that reason, in this project we propose to evaluate new molecules derived from this compound and test their antitumoral activity and how they may improve the efficacy of cancer drugs used to date. To test our hypothesis, we will used breast cancer cells and compare them to normal cells. This research will provide further evidence that FAS is an important anticancer target. Our research will identify which of the new compounds can be further used in novel clinical trials in breast cancer patients, either alone or in combination with other cancer treatments.