CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma

Autor: Prashant J. Joshi, Michael O. Idowu, Patrick Memari, Ayesha Chawla, John C. Stansfield, Kranthi Kumar Chougoni, Haemin Park, Barbara Szomju, Adam Sima, Agnes D Cororaton, Rashmi Seth, Steven R. Grossman, Keith C. Ellis
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Oncogenesis, Vol 8, Iss 10, Pp 1-7 (2019)
Oncogenesis
ISSN: 2157-9024
Popis: Ctbp2 is a uniquely targetable oncogenic transcriptional coregulator, exhibiting overexpression in most common solid tumors, and critical to the tumor-initiating cell (TIC) transcriptional program. In the “CKP” mouse pancreatic ductal adenocarcinoma (PDAC) model driven by mutant K-Ras, Ctbp2 haploinsufficiency prolonged survival, abrogated peritoneal metastasis, and caused dramatic downregulation of c-Myc, a known critical dependency for TIC activity and tumor progression in PDAC. A small-molecule inhibitor of CtBP2, 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP) phenocopied Ctbp2 deletion, decreasing tumor burden similarly to gemcitabine, and the combination of 4-Cl-HIPP and gemcitabine further synergistically suppressed tumor growth. Pharmacodynamic monitoring revealed that the 4-Cl-HIPP/gemcitabine combination induced robust and synergistic tumor apoptosis and marked downregulation of the TIC marker CD133 in CKP PDAC tumors. Collectively, our data demonstrate that targeting CtBP represents a fruitful avenue for development of highly active agents in PDAC that cooperate with standard therapy to limit both primary and metastatic tumor burden.
Databáze: OpenAIRE
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