Notch signaling pathway targeted therapy suppresses tumor progression and metastatic spread in pancreatic cancer

Cancer Lett. 2013 Jul 10;335(1):41-51. doi: 10.1016/j.canlet.2013.01.054. Epub 2013 Feb 10.

Abstract

Pancreatic ductal adenocarcinoma (PDA) remains a lethal human malignancy with historically limited success in treatment. The role of aberrant Notch signaling, which requires the constitutive activation of γ-secretase, in the initiation and progression of PDA is well defined and inhibitors of this pathway are currently in clinical trials. Here we investigated the in vivo therapeutic effect of PF-03084014, a selective γ-secretase inhibitor, alone and in combination with gemcitabine in pancreatic cancer xenografts. PF-03084014 treatment inhibited the cleavage of nuclear Notch 1 intracellular domain and Notch targets Hes-1 and Hey-1. Gemcitabine treatment showed good response but not capable of inducing tumor regressions and targeting the tumor-resident cancer stem cells (CD24(+)CD44(+) and ALDH(+) tumor cells). A combination of PF-03084014 and gemcitabine treatment resulted tumor regression in 3 of 4 subcutaneously implanted xenograft models. PF-03084014, and in combination with gemcitabine reduced putative cancer stem cells, indicating that PF-03084014 target the especially dangerous and resilient cancer stem cells within pancreatic tumors. Tumor re-growth curves plotted after drug treatments demonstrated that the effect of the combination therapy was sustainable than that of gemcitabine. Notably, in a highly aggressive orthotopic model, PF-03084014 and gemcitabine combination was effective in inducing apoptosis, inhibition of tumor cell proliferation and angiogenesis, resulting in the attenuation of primary tumor growth as well as controlling metastatic dissemination, compared to gemcitabine treatment. In summary, our preclinical data suggest that PF-03084014 has greater anti-tumor activity in combination with gemcitabine in PDA and provides rationale for further investigation of this combination in PDA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Carcinoma, Pancreatic Ductal / secondary
  • Cell Proliferation / drug effects
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives
  • Disease Progression
  • Female
  • Humans
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / prevention & control
  • Liver Neoplasms / secondary
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Nude
  • Molecular Targeted Therapy
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / metabolism*
  • Signal Transduction / drug effects
  • Tetrahydronaphthalenes / administration & dosage
  • Tumor Burden / drug effects
  • Tumor Cells, Cultured
  • Valine / administration & dosage
  • Valine / analogs & derivatives
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD
  • Receptors, Notch
  • Tetrahydronaphthalenes
  • Deoxycytidine
  • gemcitabine
  • Valine
  • nirogacestat