Notch Pathway Inhibition Using PF-03084014, a γ-Secretase Inhibitor (GSI), Enhances the Antitumor Effect of Docetaxel in Prostate Cancer

Abstract

Purpose To investigate the efficacy and mechanisms of Notch signaling inhibition as an adjuvant to docetaxel in castration-resistant prostate cancer (CRPC) using a γ-secretase inhibitor (GSI), PF-03084014. Experimental Design The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and -resistant CRPC cell lines in vitro and in murine models. Both soft tissue and bone sites were evaluated in vivo. Impacts on cell proliferation, apoptosis, cancer stem cells and angiogenesis were evaluated. Results The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and -resistant CRPC tumor growth in soft tissue and bone greater than either agent alone. Antitumor activity was associated with PF-03084014-induced inhibition of Notch pathway signaling; decreased survival signals (Cyclin E; MEK-ERK, PI3K-AKT, EGFR and NF-κB pathway; BCL-2, BCL-XL); increased apoptotic signals (BAK, BAX; cleaved-caspase 3); reduction of microvessel density; reduced epithelial mesenchymal transition; and reduction of cancer stem-like cells in the tumor. Conclusion These results reveal that PF-03084014 enhances docetaxel-mediated tumor response and provides a rationale to explore GSIs as adjunct therapy in conjunction with docetaxel for men with CRPC.

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

“…Additionally, GSI treatment delays the tumor growth of prostate cancer xenografts. Consistent with our findings, previous study has shown that the GSI PF-03084014 results in a significant decrease in tumor growth in two xenograft models of prostate cancer (PC3 and DU145) (12). PF-03084014 demonstrated an even greater antitumor effect in prostate cancer growth when combined with the chemotherapeutic agent docetaxel, which is currently in clinical use (12).…”

“…Elevated expression of the Notch ligand Jagged1 has been associated with metastatic prostate cancer (8,9), and downregulation of Notch1 and Jagged1 in human prostate cancer cell lines decreases in vitro invasion and cell growth (10). In addition, chemoresistance in human prostate cancer cells has been linked to the activation of Notch2 receptors (11,12). Despite these studies, direct evaluation of Notch receptors as drivers of aggressive prostate cancer and the relationship of Notch receptors with other commonly altered pathways in prostate tumorigenesis remain unclear.…”

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

“…49 GSI inhibitor suppressed Notch pathway and enhanced the antitumor effect of docetaxel in prostate cancer. 50 Recently, one study validated that activation of Notch-1 synergized with multiple pathways in promoting castration resistant prostate cancer. 51 Therefore, identification of precise mechanisms that regulate EMT process would likely be useful for exploring novel therapeutic approaches for the treatment of human cancers.…”

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).…”