pf-3084014 and Prostatic-Neoplasms

Prostate cancer is the second leading cause of cancer death among men in the United States. The androgen receptor (AR) antagonist enzalutamide is a Food and Drug Administration-approved drug for treatment of patients with late-stage prostate cancer and is currently under clinical study for early-stage prostate cancer treatment. After a short positive response period, tumors will develop drug resistance. In this study using RNA-Seq and bioinformatics analyses, we observed that NOTCH signaling is a deregulated pathway in enzalutamide-resistant cells.

Topics: Animals; Benzamides; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Male; Mice; Mice, Nude; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Proto-Oncogene Proteins c-myc; Receptor, Notch1; Receptor, Notch2; Signal Transduction; Tetrahydronaphthalenes; Transcription Factor HES-1; Valine; Xenograft Model Antitumor Assays

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients.

Topics: ADAM17 Protein; Amyloid Precursor Protein Secretases; Animals; Cell Line, Tumor; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p27; Humans; Male; Mice; Prostatic Neoplasms; PTEN Phosphohydrolase; Receptors, Notch; Signal Transduction; Tetrahydronaphthalenes; Up-Regulation; Valine

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.. The effect of PF-03084014 on response to docetaxel was evaluated in docetaxel-sensitive and docetaxel-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.. The combination of PF-03084014 plus docetaxel reduced both docetaxel-sensitive and docetaxel-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); reduced microvessel density; reduced epithelial-mesenchymal transition; and reduced cancer stem-like cells in the tumor.. 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.

Topics: Amyloid Precursor Protein Secretases; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Docetaxel; Drug Synergism; Humans; Male; Mice; Mice, Inbred NOD; NF-kappa B; Prostatic Neoplasms; Signal Transduction; Taxoids; Tetrahydronaphthalenes; Valine; Xenograft Model Antitumor Assays