Clinical potential of proteasome inhibition in solid tumours

Abstract

The proteasome plays a central role in the regulation of many processes critical to solid tumour growth. Proteasome inhibition activates multiple mechanisms capable of arresting tumour proliferation, tumour metastasis, and angiogenesis. In preclinical testing, the novel proteasome inhibitor bortezomib displays a unique pattern of cytotoxicity against a broad spectrum of tumour cell lines. In experimental models of breast, lung, colon, prostate, pancreatic, and ovarian cancer, bortezomib shows additive or synergistic activity when combined with chemotherapeutic agents such as irinotecan, gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, docetaxel, and doxorubicin. Bortezomib is currently being investigated both as a single agent and in combination regimens for the treatment of a broad range of solid tumours including non-small cell lung cancer (NSCLC), renal cell, breast, ovarian, prostate, colon, gastric, and pancreatic cancer. In an ongoing, single-agent phase II trial in NSCLC, one partial response and six instances of stable disease were documented in 15 evaluable patients. Pharmacodynamic studies showed inhibition of NF-κB. Two single-institution phase II trials in renal cell cancer showed four partial responses in 37 patients and one partial response in 21 patients, respectively. Randomised phase II trials of bortezomib with or without docetaxel in patients with NSCLC and with or without irinotecan in patients with colon cancer are ongoing, as are single-agent phase II studies in colon, breast, and ovarian cancer. Bortezomib is also being studied in combination with irinotecan in patients with gastro-oesophageal cancer, with gemcitabine in patients with pancreatic cancer, and with docetaxel in patients with breast and prostate cancer.