Drs. Adams and Kauffman have provided a detailed history of the development of the novel cancer therapeutic agent Velcade™ (bortezomib). This is a thorough discussion of the preclinical studies examining mechanism(s) of action, the animal studies documenting efficacy, and finally the results from the early phase I and II human clinical studies. Unlike other antineoplastic agents in the development pipeline, the mechanism of action of bortezomib is only indirectly coupled to its molecular target. While bortezomib directly inhibits the 26S proteasome, the molecular and cellular effects are far-reaching due to the requisite nature of cellular homeostasis on protein turnover by the proteasome. Therefore, bortezomib indirectly targets mediators of cell cycle progression, regulators of apoptosis, and a variety of transcription factors. Several of these targets, such as p21WAF1/CIP, p27KIP1, and the transcription factor NF-κB, have been demonstrated to be altered in transformed cells and mediate significant effects inherent in the malignant phenotype. Furthermore, the gene targets of NF-κB mediated transcriptional activation include many involved in cell survival, angiogenesis, and invasion. Bortezomib is, therefore, unique among the novel cancer therapeutics in its ability to inhibit a specific cellular target but produce wide-ranging effects on diverse molecular and cellular processes.
While some early data from the phase I and II trials have generated enthusiasm for this agent in the treatment of various cancers, an encouraging aspect of bortezomib is the diverse diseases in which it may have a therapeutic potential. Bortezomib has demonstrated significant in vitro and in vivo effects in both hematologic and solid-organ malignancies. Furthermore, inhibition of the proteasome may be effective for treatment of non-neoplastic diseases such as reperfusion injury following ischemic events (stroke or myocardial infarction)Citation[1] or autoimmune inflammatory conditions.Citation[2]Citation[3] The breadth of diseases has yet to be fully elucidated, though the key observation that proteasome inhibition has little effect on normal “unstressed/unstimulated” cellsCitation[4] adds to its potential utility in a wide range of pathophysiologic processes.
What is not presented in this manuscript is how the development of bortezomib has progressed through the joint cooperation of the biotechnology industry, academic researchers and clinicians, and the federal government. This triumvirate has become the paradigm for the development of other targeted therapies and has allowed for the rapid translation of research in the molecular genetics of cancer to novel therapies.
References
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