Proteasome Inhibitors in Cancer Therapy

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 (Velcade ) 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. 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 ) in Phase I clinical trials and in a multicentered Phase II clinical trials in patients with relapsed and refractory myeloma.