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

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 the further investigation of this combination in PDA.

New insights into pancreatic cancer stem cells

“…This was shown by the studies that overexpression of Notch1 leads to increasing in the formation of pancreatospheres along with expression of the CD44 and EpCAM CSC surface markers. Other studies reported that expression of Oct4, Nanog, and PDX1 in Notch2 positive human pancreatic adenocarcinoma cells [69] . The Oct4, Nanog and PDX1 are also considered as markers of self-renewal of pancreatic CSCs.…”

Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1–Stat3

“…PF-03084014 (PF-4014) is a GSI developed by Pfizer, which shows antitumor efficacy in hematologic, breast, colorectal, and pancreatic cancer models (13)(14)(15)(16)(17)(18), and suppresses hepatic metastases of neuroblastoma and breast cancer cells (19). Currently PF-03084014 is in phase I or phase II trials for the treatment of T-ALL, lymphoma, desmoid tumors, and fibromatosis (4,20,21).…”

Cantharidin and norcantharidin impair stemness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib

“…However, tumor growth is not sustainable without CSCs to replenish the bulk population and the tumor will eventually degenerate as bulk tumor cells are depleted. Therefore it is of paramount importance to develop targeted therapies, which eliminate CSC, thereby destroying the sole source for new tumor cells (25).…”