I. Cancer Drug Developmentn n Cancer Drug Development: Challenges in a Competitive Marketn Barry Greene and Michael Kauffmann n II. Chemistry and Cell Biology of the Proteasomen n Introduction to the Proteasome and Its Inhibitors: Biochemistry and Cell Biologyn Alfred L. Goldbergn n Structures of the Yeast Proteasome Core Particle in Complex with Inhibitorsn Michael Groll and Robert Hubern n Natural Product and Synthetic Proteasome Inhibitorsn Kyung Bo Kim and Craig M. Crewsn n Other Proteasome Inhibitorsn Carlos García-Echeverrían n The Proteasome in Cell-Cycle Regulationn Julian Adamsn n Proteasome Inhibition and Apoptosisn Simon A. Williams and David J. McConkeyn n The Proteasome and the COMPARE Algorithmn Susan L. Holbeck and Edward A. Sausvillen n III. Rationale for Proteasome Inhibitors in Cancern n The Proteasome in Cancer Biology and Therapyn Frank Pajonk and William H. McBriden n Radiosensitization and Proteasome Inhibitionn Carter Van Waes, John B. Sunwoo, William DeGraff, and James B. Mitchelln n Proteasome-Dependent Regulation of NF-kB Activation: Molecular Targeting of Chemotherapy Resistancen James C. Cusack, Jr.n n Bortezomib with Taxanesn Leonard Liebes, Bruce Ng, Yi-He Ling, and Roman Perez-Solern n Proteasome Inhibitor Therapy in a Brain Tumor Modeln Jeffrey J. Olson, Geoffrey Bowers, and Zhaobin Zhangn n Anthracyclines and Bortezomibn Robert Z. Orlowskin n TNF-Related Apoptosis-Inducing Ligand (TRAIL): Combination with Proteasome Inhibition For Anticancer Therapy?n Thomas J. Sayersn n Rationale for Combining the Proteasome Inhibitor Bortezomib with Cisplatinn Edward G. Mimnaugh and Leonard M. Neckersn n The Effects of the HIV-1 Protease Inhibitor Ritonavir on Proteasome Activity and Antigen Presentationn Marcus Groettrup, Rita deGiuli, and Gunter Schmidtken n Function(s) of the Ubiquitin-Proteasome System in Retrovirus Buddingn Ulrich Schubertn n IV. Clinical Trialsn n Preclinical Development of Bortezomib (VELCADE(TM)): Rationale for Clinical Studiesn Julian Adams, Peter J. Elliott, and Page Bouchardn n Phase I Trials: Bortezomib Alone and in Combination With Standard Chemotherapiesn Dixie-Lee W. Esseltine and David P. Schenkeinn n Clinical Molecular Diagnostics for Proteasome Inhibitors in Cancer Therapyn Jeffrey S. Ross, Gerald P. Linette, Geoffrey S. Ginsburg, William Trepicchio, Oscar Kashala, Rebecca Mosher, Jeffrey Brown, George Mulligan, Jim Deeds, and James Stecn n Phase II Trials of Bortezomib for the Treatment of Multiple Myeloman Kenneth C. Andersonn n Index
A panel of leading academic and pharmaceutical investigators takes stock of the remarkable work that has been accomplished to date with proteasome inhibitors in cancer, and examines emerging therapeutic possibilities. The topics range from a discussion of the chemistry and cell biology of the proteasome and the rationale for proteasome inhibitors in cancer to a review of current clinical trials underway. The discussion of rationales for testing proteasome inhibitors in cancer models covers the role of the proteasome in NF-kB activation, the combining of conventional chemotherapy and radiation with proteasome inhibition, notably PS-341, new proteasome methods of inhibiting viral maturation, and the role of protesome inhibition in the treatment of AIDS. The authors also document the development of bortezomib (Velcade(TM)) in Phase I clinical trials and in a multicentered Phase II clinical trials in patients with relapsed and refractory myeloma.