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ASCO Educational Book; 2009
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Realizing the Anticancer Potential of Proteasome Inhibition: The Clinical Development of Bortezomib and Second-generation Proteasome Inhibitors

Paul G. Richardson, MD, Constantine Mitsiades, MD, PhD, Jacob Laubach, MD, Dharminder Chauhan, JD, PhD, Teru Hideshima, MD, PhD, and Kenneth Anderson, MD

From the Dana-Farber Cancer Institute, Boston, MA

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

Address reprint requests to Paul G. Richardson, MD, Dana-Farber Cancer Institute, 44 Binney St, Dana 1B02, Boston MA 02115; e-mail: paul_richardson{at}dfci.harvard.edu

Overview: The "bench-to-bedside" development of the first-in-class proteasome inhibitor bortezomib has confirmed the clinical application of proteasome inhibition as an effective anticancer therapy. Preclinical studies with bortezomib and second-generation proteasome inhibitors have demonstrated activity in various malignancies, with synergy seen in combination with other agents. Bortezomib has been investigated in phase II/III trials in multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), and other hematologic and solid malignancies, with single-agent bortezomib gaining approval in relapsed MM and mantle cell lymphoma (MCL) on the basis of substantial activity in the phase III APEX and phase II PINNACLE studies, respectively. Bortezomib-based combinations have shown activity in MM, MCL, and other NHL subtypes. In relapsed MM, bortezomib retreatment is active, and bortezomib-based combinations may overcome prior chemoresistance and re-sensitize patients to previously used agents, suggesting bortezomib as a backbone of treatment. In front-line MM, phase III studies have demonstrated superiority of bortezomib-based combinations compared with previous standards of care; bortezomib gained approval in front-line MM on the basis of the VISTA study of bortezomib plus melphalan-prednisone. The safety profile of bortezomib has been well characterized; toxicities are predictable and manageable, with peripheral neuropathy as an important side effect, which appears to be mechanism-based. Second-generation proteasome inhibitors are at earlier developmental stages, with an expanding program of studies in various malignancies. Carfilzomib has shown encouraging activity in relapsed MM in phase II studies with preliminary safety data showing minimal peripheral neuropathy. Early data with NPI-0052 and CEP-18770 are also promising. Additionally, novel combination approaches, as well as novel agents targeting processes upstream of the proteasome, are in development.