Clinical update: novel targets in gynecologic malignancies.

The proteasome inhibitor bortezomib has shown activity in chemotherapy-resistant tumors and is approved for treatment of multiple myeloma. The critical component of bortezomib's antitumor activity is the inhibition of nuclear factor-kappa B (NF-kappaB). Patients with ovarian cancer respond to initial platinum-based chemotherapy, such as cisplatin. However, these agents have been shown to induce tumor cell survival by inducing NF-kappaB activity. Phase I trials of bortezomib in solid tumors, including ovarian cancer, are summarized and examined to determine if the compound can overcome the impact of chemoresistance. In one trial of single-agent bortezomib in advanced malignancies, it was deemed a safe and manageable drug with potential efficacy in solid tumors. A second phase I trial explored inhibition of NF-kappaB with bortezomib to see if the drug rendered platinum agents more sensitive in ovarian cancer patients. Seven of the nine patients in the study had major responses to the combination of carboplatin and bortezomib. The two trials indicate promising results for bortezomib in patients with solid tumors and patients with recurrent ovarian cancer, but further investigation is warranted.