Abstract 3901: Therapeutic targeting of C-terminal binding protein: a key dependency for polyposis and cancer stem cell activity in APC mutant neoplasia
| Autor: | Evan T. Sumner, Ayesha Chawla, Steven R. Grossman, Barbara Szomju, Agnes D Cororaton, Rashmi Seth |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Cancer Research. 77:3901-3901 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/1538-7445.am2017-3901 |
| Popis: | The C terminal binding proteins (CtBP) 1 and 2 are a family of transcriptional co-repressors overexpressed in a variety of cancers, and are frequently associated with poor prognosis and chemoresistance. CtBP has also been characterized in cell culture models as drivers of migration/invasion and epithelial-mesenchymal transition. CtBP mediates its transcriptional corepressor activity via its dehydrogenase domain, and inhibition of this domain interferes with CtBP oncogenic functions. The role of CtBP in APC mutant neoplasia remains obscure even though APC is responsible for degradation of both β-catenin and CtBP in suppressing colorectal tumorigenesis. Our prior work demonstrates that CtBP proteins can be effectively therapeutically targeted with substrate analogues of their intrinsic dehydrogenase domains. We now observe that pharmacologic inhibition of CtBP using either the 1st generation inhibitor 2-keto-4-methylthiobutyrate (MTOB) or the 2nd generation inhibitor hydroxyimino-3-phenylpropanoic acid (HIPP) significantly reduces the burden of intestinal polyps in the Apcmin mouse model of the human cancer predisposition syndrome Familial Adenomatous Polyposis. The number of intestinal polyps in mice with CtBP2 inhibitors were significantly lower (21 polyps/mouse for MTOB, 15 polyps/mouse for HIPP) as compared with vehicle treated mice (45 polyps/mouse) with a P value Citation Format: Ayesha T. Chawla, Agnes Cororaton, Rashmi Seth, Barbara Szomju, Evan T. Sumner, Steven R. Grossman. Therapeutic targeting of C-terminal binding protein: a key dependency for polyposis and cancer stem cell activity in APC mutant neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3901. doi:10.1158/1538-7445.AM2017-3901 |
| Databáze: | OpenAIRE |
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