Abstract 3069: DSP-0692, a novel and selective stearoyl-CoA desaturase (SCD) inhibitor targeting cancer stem cells
| Autor: | Eiji Sugaru, Yudai Furuta, Miki Hashizume, Yuichi Fukunaga, Hiroki Umehara, Tojo Shingo, Futoshi Hasegawa, Manabu Watanabe, Hitoshi Ban, Tsuguteru Otsubo |
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| Rok vydání: | 2018 |
| Předmět: | |
| Zdroj: | Cancer Research. 78:3069-3069 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | In recent years evidence has accumulated in support of the cancer stem cells (CSCs) model in cancer chemotherapy resistance, highlighting the urgency and necessity of identifying CSC-specific targets for new cancer therapeutics. SCD, a key enzyme for lipid metabolism, is overexpressed in various types of cancer and plays an important role in cancer cell proliferation. In particular, recent studies have implicated SCD involved also in the maintenance of CSCs. Here, the identification and the functional characterization of DSP-0692, a novel and selective SCD inhibitor, is reported, using various pharmacological approaches to address the mechanism of SCD inhibition in cancer cells and its efficacy in preclinical tumor models. In these preclinical models, DSP-0692 inhibited human SCD activity with low nanomolar IC50 values. SCD expression was induced in tumor cells cultured in sphere conditions, which were resistant to conventional agents within therapeutic concentration. DSP-0692 showed strong growth inhibition when tumor cells were cultured in sphere conditions, but had little impact on cells cultured under normal two-dimensional conditions. In addition, DSP-0692 inhibited the CSC-related signaling pathway and decreased CSC markers expression in tumor cells as well as in tumor tissues. Treatment of DSP-0692 as single agent suppressed tumor growth in multiple models. Furthermore, this efficacy was enhanced in combination with conventional chemotherapies in those tumor models. Of note, SCD protein expression in tumor tissues was useful as a predictive marker for the susceptibility to DSP-0692 treatment. Taken together, these data suggest that inhibition of fatty acid desaturation by DSP-0692 could be a new therapeutic strategy in SCD-positive cancer, with potential to overcome resistance to standard chemotherapies. Citation Format: Eiji Sugaru, Yudai Furuta, Yuichi Fukunaga, Hiroki Umehara, Tsuguteru Otsubo, Manabu Watanabe, Futoshi Hasegawa, Shingo Tojo, Miki Hashizume, Hitoshi Ban. DSP-0692, a novel and selective stearoyl-CoA desaturase (SCD) inhibitor targeting cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3069. |
| Databáze: | OpenAIRE |
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