Recent advances in understanding the complex biology of the
ubiquitin-
proteasome pathway have led to the identification of many potentially 'drugable' targets within this pathway. One such inhibitor,
bortezomib (formerly known as
PS341), has proven to be an effective reversible inhibitor of the chymotryptic
protease in the
26S proteasome.
Proteasome inhibitors represent a new approach for the treatment of many forms of
cancer, especially select
hematological malignancies. The
proteasome plays an important role in regulating the availability of different intracellular
proteins. While only some of the consequences of inhibiting this activity are understood, a growing amount of data suggests that inhibition of the
proteasome is associated with a remarkable panoply of different
biological effects that include cell cycle arrest, apoptosis, changes in cell surface adhesion markers, and an increased sensitivity to standard
chemotherapy and
radiation therapy.
Bortezomib was recently approved by the US FDA for the treatment of relapsed or refractory
multiple myeloma. In addition,
bortezomib has also shown encouraging results in the treatment of select types of non-Hodgkin
lymphomas (NHLs). Ongoing phase II clinical trials in pretreated patients are exploring
bortezomib in different histologies of NHLs and in combination with conventional
chemotherapy. Preliminary data have shown interesting activity, especially in patients with follicular, marginal zone, and
mantle cell lymphoma; in these populations, durable complete and partial remissions have been reported. The toxicity profile of this
drug, coupled with its unusual mechanism of action, make it a potentially important agent warranting further preclinical and clinical attention. However, many unanswered questions remain regarding how best to employ
bortezomib in the conventional treatment of
lymphoma. The apparent lack of activity in different subtypes of
lymphoma, such as
small lymphocytic lymphoma/
chronic lymphocytic leukemia and
diffuse large B-cell lymphoma, as well as a lack of understanding about the best way to combine
bortezomib with standard
therapies for indolent NHLs, raises important questions regarding the mechanistic basis for its effects. We will undoubtedly need to understand these effects better in order to fully exploit the potential of this new class of drugs.