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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Ctbp2 is an oncogenic transcriptional coregulator overexpressed in solid tumors.
• Ctbp2 is critical for tumor-initiating cell (TIC) transcriptional programs and PDAC progression.
• Mutant K-Ras drives pancreatic ductal adenocarcinoma (PDAC) in the CKP mouse model.

Purpose of the Study:

• To investigate the therapeutic potential of targeting Ctbp2 in PDAC.
• To evaluate the efficacy of a CtBP2 inhibitor (4-Cl-HIPP) alone and in combination with gemcitabine.
• To assess the impact on tumor burden, metastasis, and TIC markers.

Main Methods:

• Utilized the CKP mouse model of PDAC.
• Administered Ctbp2 haploinsufficiency and the small-molecule inhibitor 4-Cl-HIPP.
• Combined 4-Cl-HIPP with gemcitabine chemotherapy.
• Monitored tumor growth, metastasis, c-Myc, and CD133 expression.

Main Results:

• Ctbp2 haploinsufficiency prolonged survival and reduced metastasis in PDAC models.
• 4-Cl-HIPP phenocopied Ctbp2 deletion, decreasing tumor burden similarly to gemcitabine.
• The combination of 4-Cl-HIPP and gemcitabine synergistically suppressed tumor growth, induced apoptosis, and downregulated CD133.

Conclusions:

• Targeting CtBP2 is a promising therapeutic strategy for PDAC.
• Combination therapy with CtBP2 inhibitors and standard chemotherapy can limit primary and metastatic tumor burden.
• This approach offers a novel avenue for treating pancreatic cancer by targeting TICs.