Proteasome Inhibitors in Cancer Therapy (Cancer Drug Discovery and Development)

Immediately upon the discovery some ten years ago that inhibition of the proteasome in cultured cells, mostly of tumor origin, caused the programmed cell death machinery to ramp up, it became imperative to investigate proteasome inhibition as a possible treatment for human cancers. In Proteasome Inhibitors in Cancer Therapy, Julian Adams, the leader in developing the field, brings together a panel of highly experienced academic and pharmaceutical investigators to take stock of the remarkable work that has been accomplished to date, and examine emerging therapeutic possibilities for proteasome inhibitors in cancer. 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 the very empirical and practical development of rationales to test 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 proteasome inhibition in the treatment of AIDS. The authors also document the development of bortezomib (VelcadeTM) through multicentered clinical trials in patients with relapsed and refractory myeloma to FDA approval, and describe how modern pharmacogenomic tools can be used to predict which patients will respond to such proteasome inhibitor therapy. Additional chapters on the proteasome's basic biochemistry review its mechanism in the cell cycle and apoptosis and suggest opportunities for using proteasome inhibitors to find additional medicinal targets. Authoritative and illuminating, Proteasome Inhibitors in Cancer Therapy makes clear that proteasome inhibition should prove a fertile area for the many future discoveries that will provide relief of suffering and extend the quality of life of patients afflicted with cancer and other debilitating diseases. 1. Cancer Drug Development : Challenges In A Competitive Market / Barry Greene And Michael Kauffman -- 2. Introduction To The Proteasome And Its Inhibitors : Biochemistry And Cell Biology / Alfred L. Goldberg -- 3. Structures Of The Yeast Proteasome Core Particle In Complex With Inhibitors / Michael Groll And Robert Huber -- 4. Natural Product And Synthetic Proteasome Inhibitors / Kyung Bo Kim And Craig M. Crews -- 5. Other Proteasome Inhibitors / Carlos Garcia-echeverria -- 6. The Proteasome In Cell-cycle Regulation / Julian Adams -- 7. Proteasome Inhibition And Apoptosis / Simon A. Williams And David J. Mcconkey -- 8. The Proteasome And The Compare Algorithm / Susan L. Holbeck And Edward A. Sausville -- 9. The Proteasome In Cancer Biology And Therapy / Frank Pajonk And William H. Mcbride -- 10. Radiosensitization And Proteasome Inhibition / Carter Van Waes, John B. Sunwoo, William Degraff And James B. Mitchell -- 11. Proteasome-dependent Regulation Of Nf-[kappa]b Activation : Molecular Targeting Of Chemotherapy Resistance / James C. Cusack, Jr. -- 12. Bortezomib With Taxanes / Leonard Liebes, Bruce Ng, Yi-he Ling And Roman Perez-soler -- 13. Proteasome Inhibitor Therapy In A Brain Tumor Model / Jeffrey J. Olson, Geoffrey Bowers And Zhaobin Zhang -- 14. Anthracyennes And Bortezomib / Robert Z. Orlowski -- 15. Tnf-related Apoptosis-inducing Ligand (trail) : Combination With Proteasome Inhibition For Anticancer Therapy? / Thomas J. Sayers -- 16. Rationale For Combining The Proteasome Inhibitor Bortezomib With Cisplatin / Edward G. Mimnaugh And Leonard M. Neckers -- 17. The Effects Of The Hiv-1 Protease Inhibitor Ritonavir On Proteasome Activity And Antigen Presentation / Marcus Groettrup, Rita De Giuli And Gunter Schmidtke -- 18. Function(s) Of The Ubiquitin-proteasome System In Retrovirus Budding / Ulrich Schubert -- 19. Preclinical Development Of Bortezomib (velcade) : Rationale For Clinical Studies / Julian Adams, Peter J. Elliott And Page Bouchard -- 20. Phase I Trials : Bortezomib Alone And In Combination With Standard Chemotherapies / Dixie-lee W. Esseltine And David P. Schenkein -- 21. Clinical Molecular Diagnostics For Proteasome Inhibitors In Cancer Therapy / Jeffrey S. Ross, Gerald P. Linette, Geoffrey S. Ginsburg, William Trepicchio, Oscar Kashala, Rebecca Mosher, Jeffrey Brown, George Mulligan, Jim Deeds And James Stec -- 22. Phase Ii Trials Of Bortezomib For The Treatment Of Multiple Myeloma / Kenneth C. Anderson. Edited By Julian Adams. Includes Bibliographical References And Index. Front Matter....Pages i-xv Front Matter....Pages 1-1 Cancer Drug Development....Pages 3-13 Front Matter....Pages 15-15 Introduction to the Proteasome and its Inhibitors....Pages 17-38 Structures of the Yeast Proteasome Core Particle in Complex with Inhibitors....Pages 39-46 Natural Product and Synthetic Proteasome Inhibitors....Pages 47-63 Other Proteasome Inhibitors....Pages 65-75 The Proteasome in Cell-Cycle Regulation....Pages 77-84 Proteasome Inhibition and Apoptosis....Pages 85-98 The Proteasome and the COMPARE Algorithm....Pages 99-107 Front Matter....Pages 109-109 The Proteasome in Cancer Biology and Therapy....Pages 111-121 Radiosensitization and Proteasome Inhibition....Pages 123-130 Proteasome-Dependent Regulation of NF-κB Activation....Pages 131-143 Bortezomib with Taxanes....Pages 145-159 Proteasome Inhibitor Therapy in a Brain Tumor Model....Pages 161-170 Anthracyclines and Bortezomib....Pages 171-180 TNF-Related Apoptosis-Inducing Ligand (TRAIL)....Pages 181-191 Rationale for Combining the Proteasome Inhibitor Bortezomib with Cisplatin....Pages 193-205 Effects of the HIV-1 Protease Inhibitor Ritonavir on Proteasome Activity and Antigen Presentation....Pages 207-216 Function(s) of the Ubiquitin—Proteasome System in Retrovirus Budding....Pages 217-230 Front Matter....Pages 231-231 Preclinical Development of Bortezomib (VELCADETM)....Pages 233-269 Phase I Trials....Pages 271-282 Front Matter....Pages 231-231 Clinical Molecular Diagnostics for Proteasome Inhibitors in Cancer Therapy....Pages 283-299 Phase II Trials of Bortezomib for the Treatment of Multiple Myeloma....Pages 301-305 Back Matter....Pages 307-313

A panel of leading academic and pharmaceutical investigators takes sk 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 (VelcadeTM) in Phase I clinical trials and in a multicentered Phase II clinical trials in patients with relapsed and refractory myeloma.

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 (VelcadeTM) in Phase I clinical trials and in a multicentered Phase II clinical trials in patients with relapsed and refractory myeloma. Takes stock of the work that has been accomplished with proteasome inhibitors in cancer, and examines various therapeutic possibilities. This title covers topics ranging from a discussion of the chemistry and cell biology of the proteasome and the rationale for proteasome inhibitors in cancer to a review of clinical trials underway. In the 1940s, a leak from a leftover canister of mustard gas prompted scientists to take a closer look at the myelosuppressive implications of nitrogen mustard for treating acute leukemia (then deemed a fatal disease).