Proteasome inhibition as a novel approach to cancer therapy

J Adams, PhD

Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts

The ubiquitin-proteasome pathway is the primary system for cellular protein degradation. Proteasome substrates are first ubiquitinated, and tight regulation of this step confers specificity on proteasome-mediated protein degradation. Controlled degradation by the proteasome is a key regulatory step in the execution of many cellular processes, including cell proliferation and apoptosis. Ubiquitinated regulatory proteins accumulate in cells treated with a proteasome inhibitor and cease cell-cycle progression. This response is more dramatic in transformed cells, which, after cell-cycle arrest, eventually undergo apoptosis. To study the regulatory role of the proteasome, we developed potent and highly specific peptidyl boronate proteasome inhibitors, including PS-341, the first such drug to enter clinical trials. A wide variety of tumor cell lines are sensitive to PS-341-- either as a single agent or in combination with other cytotoxic drugs. In mouse xenograft models, PS-341 is effective against prostate, pancreatic, Lewis lung, breast, and colon cancers. Common drug resistance mechanisms are insufficient to protect against PS-341-mediated apoptosis: drug-resistant cell lines are still sensitive to PS-341, and PS-341 is a poor substrate for drug efflux pumps. In addition, genetic inactivation of programmed cell death mechanisms (eg, by inactivation of p53 or overexpression of Bcl-2) does not confer protection to PS-341, indicating that PS-341 triggers multiple apoptotic pathways. In phase I trials, twice-weekly PS-341 regimens that achieve >70% proteasome inhibition have biologic activity in several cancers and have manageable toxicities. In addition to continued phase I studies in solid tumors and hematologic cancers, PS-341 is being evaluated in phase II trials.

KEY WORDS: chronic lymphocytic leukemia, drug resistance, multiple myeloma, solid tumors, ubiquitin-proteasome pathway.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Multidrug Resistance - MDR.