Roberto Piva1,2,3, Bruce Ruggeri4, Michael Williams4, Giulia Costa1, Ilaria Tamagno1, Dario Ferrero5, Valentina Giai5, Marta Coscia1,5, Silvia Peola1,5, Massimo Massaia1,5, Gabriella Pezzoni6, Cecilia Allievi6, Nicoletta Pescalli6, Mara Cassin6, Stefano di Giovine6, Paola Nicoli6, Paola de Feudis6, Ivan Strepponi6, Ilaria Roato6, Riccardo Ferracini7
1Center for Experimental Research and Medical Studies (CeRMS), Torino, Italy and
2Department of Biomedical Sciences and Human Oncology, University of Torino, Torino, Italy
3Department of Pathology and New York University Cancer Center, New York University School of Medicine, New York;
4Discovery Research, Cephalon, West Chester, PA;
5Hematology Division, University of Torino, Torino, Italy;
6Sede Secondaria Della Cell Therapeutics, Bresso, Italy;
7Orthopedic and Traumatology, San Giovanni Battista of Torino, Torino, Italy;
Tóm tắt
Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-κB (NF-κB) activity and the expression of several NF-κB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL–induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow–derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.
