Pharmacological Disruption of the Notch1 Transcriptional Complex Inhibits Tumor Growth by Selectively Targeting Cancer Stem Cells.

Autor:	Alvarez-Trotta A; The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida.; Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida., Guerrant W; StemSynergy Therapeutics Inc. Miami, Florida., Astudillo L; The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida.; Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida., Lahiry M; The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida.; Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida., Diluvio G; The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida.; Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida., Shersher E; The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida.; Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida., Kaneku H; Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida., Robbins DJ; The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida.; Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida., Orton D; StemSynergy Therapeutics Inc. Miami, Florida., Capobianco AJ; The DeWitt Daughtry Family Department of Surgery, Molecular Oncology Program, Miller School of Medicine, University of Miami, Miami, Florida. tcapobianco@med.miami.edu.; Sylvester Cancer Center, Miller School of Medicine, University of Miami, Miami, Florida.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2021 Jun 15; Vol. 81 (12), pp. 3347-3357. Date of Electronic Publication: 2021 Apr 05.
DOI:	10.1158/0008-5472.CAN-20-3611
Abstrakt:	In many human cancers, deregulation of the Notch pathway has been shown to play a role in the initiation and maintenance of the neoplastic phenotype. Aberrant Notch activity also plays a central role in the maintenance and survival of cancer stem cells (CSC), which underlie metastasis and resistance to therapy. For these reasons, inhibition of Notch signaling has become an exceedingly attractive target for cancer therapeutic development. However, attempts to develop Notch pathway-specific drugs have largely failed in the clinic, in part due to intestinal toxicity. Here, we report the discovery of NADI-351, the first specific small-molecule inhibitor of Notch1 transcriptional complexes. NADI-351 selectively disrupted Notch1 transcription complexes and reduced Notch1 recruitment to target genes. NADI-351 demonstrated robust antitumor activity without inducing intestinal toxicity in mouse models, and CSCs were ablated by NADI-351 treatment. Our study demonstrates that NADI-351 is an orally available and potent inhibitor of Notch1-mediated transcription that inhibits tumor growth with low toxicity, providing a potential therapeutic approach for improved cancer treatment. SIGNIFICANCE: This study showcases the first Notch1-selective inhibitor that suppresses tumor growth with limited toxicity by selectively ablating cancer stem cells. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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