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

Autor:	Chawla AT; C. Kenneth and Diane Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, 23298, USA., Chougoni KK; C. Kenneth and Diane Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, 23298, USA., Joshi PJ; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA., Cororaton AD; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA., Memari P; Department of Pathology, Virginia Commonwealth University, Richmond, VA, 23298, USA., Stansfield JC; Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, 23298, USA., Park H; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA., Seth R; Department of Surgery, Virginia Commonwealth University, Richmond, VA, 23298, USA., Szomju B; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA., Sima AP; Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, 23298, USA.; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA., Idowu MO; Department of Pathology, Virginia Commonwealth University, Richmond, VA, 23298, USA.; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA., Ellis KC; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.; Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA., Grossman SR; Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA. steven.grossman@vcuhealth.org.; VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA. steven.grossman@vcuhealth.org.
Jazyk:	angličtina
Zdroj:	Oncogenesis [Oncogenesis] 2019 Oct 04; Vol. 8 (10), pp. 55. Date of Electronic Publication: 2019 Oct 04.
DOI:	10.1038/s41389-019-0163-x
Abstrakt:	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:	MEDLINE
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