Journal of Clinical Oncology, Vol 23, No 3 (January 20), 2005: pp. 630-639
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.11.030
Proteasome Inhibition As a Novel Therapeutic Target in Human Cancer
S. Vincent Rajkumar,
Paul G. Richardson,
Teru Hideshima,
Kenneth C. Anderson
From the Division of Hematology, Mayo Clinic, Rochester, MN; and Dana-Farber Cancer Institute, Boston, MA
Address reprint requests to S. Vincent Rajkumar, MD, Division of Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: rajks{at}mayo.edu
The 26S proteasome is a large intracellular adenosine 5'-triphosphate–dependent protease that identifies and degrades proteins tagged for destruction by the ubiquitin system. The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis. Dysregulation of this enzymatic system may also play a role in tumor progression, drug resistance, and altered immune surveillance, making the proteasome an appropriate and novel therapeutic target in cancer. Bortezomib (formerly known as PS-341) is the first proteasome inhibitor to enter clinical practice. It is a boronic aid dipeptide that binds directly with and inhibits the enzymatic complex. Bortezomib has recently shown significant preclinical and clinical activity in several cancers, confirming the therapeutic value of proteasome inhibition in human malignancy. It was approved in 2003 for the treatment of advanced multiple myeloma (MM), with approximately one third of patients with relapsed and refractory MM showing significant clinical benefit in a large clinical trial. Its mechanism of action is partly mediated through nuclear factor-kappa B inhibition, resulting in apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma. Additional mechanisms include c-Jun N-terminal kinase activation and effects on growth factor expression. Several clinical trials are currently ongoing in MM as well as several other malignancies. This article discusses proteasome inhibition as a novel therapeutic target in cancer and focuses on the development, mechanism of action, and current clinical experience with bortezomib.
Supported in part by grant Nos. CA85818, CA93842, CA100080, CA62242, CA50947, and CA78378 from the National Cancer Institute, Bethesda, MD. Also supported in part by the Multiple Myeloma Research Foundation (S.V.R. and K.C.A.), Goldman Philanthropic Partnerships (S.V.R.), the Leukemia and Lymphoma Society (S.V.R.), the Myeloma Research Fund (K.C.A. and T.H.), and the Doris Duke Distinguished Clinical Research Award (K.C.A.).
The authors have received research support from Millennium Pharmaceuticals. K.C.A. and P.G.R. have received payments from Millennium Pharmaceuticals for lectures and serving on its advisory board.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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