Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer

Oncotarget. 2014 Nov 30;5(22):11038-53. doi: 10.18632/oncotarget.2701.

Abstract

Pancreatic ductal adenocarcinoma (PDA) continues to be one of the deadliest cancers due to the absence of effective treatment. Curaxins are a class of small molecules with anti-cancer activity demonstrated in different models of cancer in mice. The lead curaxin compound, CBL0137, recently entered Phase I clinical trials. Curaxins modulate several important signaling pathways involved in the pathogenesis of PDA through inhibition of chromatin remodeling complex FACT. FACT is overexpressed in multiple types of tumor, with one of the highest rate of overexpression in PDA (59%). In this study, the efficacy of CBL0137 alone or in combination with current standard of care, gemcitabine, was tested against different models of PDA in vitro and in mouse models. It was found that CBL0137 alone is a potent inducer of apoptosis in pancreatic cancer cell lines and is toxic not only for proliferating bulk tumor cells, but also for pancreatic cancer stem cells. In mice, CBL0137 was effective against several PDA models, including orthotopic gemcitabine resistant PANC-1 model and patient derived xenografts, in which CBL0137 anti-tumor effect correlated with overexpression of FACT. Moreover, we observed synergy of CBL0137 with gemcitabine which may be explained by the ability of CBL0137 to inhibit several transcriptional programs induced by gemcitabine, including NF-kappaB response and expression of ribonucleotide reductase, one of the targets of gemcitabine in cells. This data suggest testing of CBL0137 efficacy in Phase II trial in PDA patients alone and in combination with gemcitabine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Carbazoles / administration & dosage
  • Carbazoles / pharmacology*
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Disease Models, Animal
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / pathology*
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Substances

  • CBLC137
  • Carbazoles
  • Deoxycytidine
  • gemcitabine