Novel targeted therapies in epithelial ovarian cancer: from basic research to the clinic

Abstract

The development of new molecularly targeted therapies represents a high priority for the treatment of epithelial ovarian cancer. P-glycoprotein overexpression has been associated with multidrug resistance, and the use of multidrug resistance modulators, such as valspodar, is being explored in combination with chemotherapy. Human epidermal receptor (HER) family members are attractive targets for biological therapies. The addition of erlotinib or cetuximab to first–line paclitaxel- plus carboplatin-based chemotherapy is feasible and well tolerated. Gefitinib is able to inhibit the proliferation of ovarian clear-cell carcinoma in in vitro and in vivo experimental models. Single-agent trastuzumab has a limited value for recurrent epithelial ovarian cancer owing to the low frequency of HER2 overexpression and the low rate of objective responses among HER2-overexpressing patients. A Gynecologic Oncology Group Phase II trial of the proteasome inhibitor bortezomib in recurrent epithelial ovarian cancer is currently ongoing, and the combination of bortezomib and chemotherapeutic agents should be assessed. The mammalian target of rapamycin (mTOR) plays an important role in stimulating the translation of mRNAs encoding key proteins for cell growth and angiogenesis, and mTOR inhibitors, such as AP-23573 (ARIAD), deserve to be tested in selected epithelial ovarian cancer patients. The addition of intraperitoneal treatment with adenovirus containing human wild-type p53 to standard paclitaxel- plus carboplatin-based chemotherapy failed to improve the clinical outcome of patients with mutated p53 epithelial ovarian cancer. The Gynecologic Oncology Group is conducting a Phase II trial of single-agent bevacizumab (antivascular endothelial growth factor monoclonal antibody) in platinum-resistant disease. In conclusion, emerging drugs for epithelial ovarian cancer include agents designed to overcome chemoresistance, HER-targeting agents, proteasome inhibitors, mTOR inhibitors and angiogenesis inhibitors. A new paradigm of treatment could consist of chemotherapy combined with a biological agent for six cycles, and followed by chronic maintenance therapy with the biological agent alone. Advances in genomics and proteomics will elucidate the molecular mechanisms of ovarian carcinogenesis, which will hopefully lead to individualized molecular medicine in the next years.

Keywords::

• angiogenesis
• apoptosis
• chemoresistance
• extracellular signal-regulated protein kinase
• human epidermal receptor
• mammalian target of the rapamycin
• p53 gene
• proteasome
• vascular endothelial growth factor

Notes

ERK: Extracellular signal-regulated protein kinase; MAPK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin.

DIABLO: Direct IAP-binding protein with low PI; Smac: Second mitochondria-derived activator of caspase; TRAIL: Tumor necrosis factor-related apoptosis-inducing ligand.

VEGF: Vascular endothelial growth factor.