pf-3084014 and Adenocarcinoma

Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014.. A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting.. We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active β-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours.. This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.

Topics: Adenocarcinoma; Adult; Aged; Amyloid Precursor Protein Secretases; Animals; Cell Growth Processes; Colorectal Neoplasms; Enzyme Inhibitors; Female; Gene Knockdown Techniques; HCT116 Cells; Humans; Mice; Mice, Nude; Middle Aged; Random Allocation; Receptors, Notch; Tetrahydronaphthalenes; Valine; Wnt Signaling Pathway; Xenograft Model Antitumor Assays