Bortezomib as a Potential Treatment for Prostate Cancer

Abstract

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 androgenindependent 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 B effector. This Phase I trial and preclinical studies support additional testing of bortezomib in combination with radiation or chemotherapy for androgen-independent prostate cancer.

Activation of nuclear factor-κB in human prostate carcinogenesis and association to biochemical relapse

“…Also, dexamethasone, a glucocorticoid used commonly for prostate cancer treatment, disrupts the NF-kB-IL-6 pathway and this is thought to mediate the antitumour effect (Nishimura et al, 2001). Finally, recent evidence in a phase I clinical trial has suggested that the proteasome inhibitor bortezomib has activity against human prostate cancer and reduces the expression of serum IL-6 and PSA levels in some patients (Papandreou and Logothetis, 2004). This is relevant here since the degradation of the inhibitor of NF-kB, IkB, is dependent on the ubiquitin -proteasome pathway, and proteasome inhibition results in inhibition of NF-kB (Elliott and Ross, 2001;Adams, 2004;Papandreou and Logothetis, 2004).…”

Predictors of mortality after androgen‐deprivation therapy in patients with rapidly rising prostate‐specific antigen levels after local therapy for prostate cancer

“…This lower risk group may benefit from the addition of less toxic systemic agents to achieve longterm control and may be considered for randomized Phase II trials examining the impact of promising novel systemic therapies in addition to ADT on the time to PSA failure. Some of these novel agents include Thalidomide, 20,21 endothelin receptor A antagonists, 22,23 proteasome inhibitors, 24,25 and vaccines. [26][27][28] The agents that show the longest prolongation in time to PSA failure with minimal toxicity then may be considered for study in future Phase III trials.…”

Inhibition of Akt pathways in the treatment of prostate cancer

“…Akt causes the NFkB binding protein, IkB, to release NFkB, which then translocates to the nucleus where it transcribes multiple genes involved with proliferation, inflammation, cell adhesion, stress response and antiapoptosis. 15 NFkB also increases expression of matrix metalloproteinases, which are frequently elevated in CaP specimens and may play a role in promoting invasion and metastasis.…”