Targeted Therapy for Ovarian Cancer

Targeted Therapy for Ovarian Cancer: Introduction

Ovarian cancer is the most common cause of mortality of tumors fromgynecologic origin and is often diagnosed after patients have already progressed to advanced disease stage. The current standard of care for treatment of ovarian cancer includes cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately,many patients will recur and ultimately die from their disease. Targeted therapies have been evaluated in ovarian cancer as a method to overcome resistant disease.

Targeted Therapy for Ovarian Cancer: VEGF-A

Angiogenesis is the development of new blood vessels in areas of new tissue growth. It is also an important process that occurs almost universally in solid tumors as a response to the expansion of the cancer mass. Molecular markers of angiogenesis have been studied in ovarian cancer. It is found the importance of the VEGF pathway in angiogenesis. Bevacizumab is a monoclonal antibody directed against VEGF-A. Researches and clinical trials have been made and apparent responces have been revealed.

Targeted Therapy for Ovarian Cancer: EGFR

Epidermal growth factor receptor (EGFR) is overexpressed in 70% of cancers and is associated with chemoresistance, poor prognosis, and advanced disease at presentation. The mechanism of growth factor receptors is via activation of the intracellular tyrosine kinase domain, which triggers downstream targets and subsequently cell proliferation and survival. Preclinical studies suggested that inhibiting this target might reverse chemoresistance and demonstrate antitumor activity. Unfortunately,clinical trials evaluating drugs affecting these pathways, such as studies of EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) and monoclonal antibodies directed against EGFR (cetuximab, panitumumab, and matuzumab), have not been met with significant success, showing only modest efficacy

Targeted Therapy for Ovarian Cancer: Multikinase Inhibitors

Sorafenib is an oral multikinase inhibitor that targets the mitogen-activated protein kinase (MAPK) pathway or Raf/MEK/ERK pathway. This drug also inhibits VEGFR- 1, -2, and -3 and platelet-derived growth factor receptor (PDGFR) beta tyrosine kinase activity. Sorafenib is currently FDA-approved for treatment of advanced renal cell cancer, and the biologic rationale for attempting its use in other solid tumors is the fact that MAPK pathway is well conserved evolutionarily and may serve as a central and common target.

Targeted Therapy for Ovarian Cancer: PARP

Poly(ADP-ribose) polymerase (PARP) is an enzyme involved in repair of DNA single-strand breaks using the base excision
repair pathway. A recent review by Yap et al. detailed the mechanism by which PARP inhibition can lead to cancer cell death. Inhibition of PARP leads to the accumulation of DNA single-strand breaks, which may subsequently lead to DNA double-strand breaks at replication forks. In normal cells, double-strand breaks would be repaired in part by error-free homologous recombination DNA repair mechanisms. Olaparib is an oral small-molecular PARP inhibitor. A randomized phase II trial comparing olaparib (200 or 400 mg orally twice daily) with pegylated liposomal doxorubicin (50mg/m2 monthly intravenous) in patients with BRCA-mutated ovarian cancer with a platinum-free interval of 0–12 months is currently underway (NCT00628251).

Targeted Therapy for Ovarian Cancer: Reference

Willmott L J et al. Targeted therapy in ovarian cancer[J]. Journal of oncology, 2010, 2010.