Androgen ablation and
chemotherapy provide effective palliation for most patients with advanced
prostate cancer, but eventually progressing
androgen-independent
prostate cancer threatens the lives of patients usually within a few years, mandating improvement in
therapy.
Proteasome inhibition has been proposed as a
therapy target for the treatment of solid and
hematological malignancies. The
proteasome is a ubiquitous
enzyme complex that is a hub for the regulation of many intracellular regulatory pathways; because of its essential function, this
enzyme has become a new target for
cancer treatment. Studies with
bortezomib (
VELCADE, formerly known as
PS-341) and other
proteasome inhibitors indicate that
cancer cells are especially dependent on the
proteasome for survival, and several mechanisms used by
prostate cancer cells require
proteasome function.
Bortezomib has been studied extensively in vitro and in vivo, and anticancer activity has been seen in cell and animal models for several solid
tumor types, including
prostate cancer. A Phase I trial to determine the maximum tolerated dose of once-weekly
bortezomib has been completed. This trial included a large fraction of patients with
androgen-independent
prostate cancer. The maximum tolerated dose was reached at 1.6 mg/m(2). A correlation was seen among
bortezomib dose,
proteasome inhibition, and positive modulation of serum
prostate-specific antigen. There was also evidence of down-regulation of serum
interleukin 6, a downstream
nuclear factor kappaB effector. This Phase I trial and preclinical studies support additional testing of
bortezomib in combination with radiation or
chemotherapy for
androgen-independent
prostate cancer.