Table 3.

Examples of targeted molecular cancer therapeutics for epithelial ovarian cancer

Category	Target molecule	Agent(s)	References
Angiogenesis	Vascular endothelial growth factor	Bevacizumab	[71, 85]
Function	Bevacizumab is a humanized recombinant monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) receptor binding
Efficacy	A clinical trial of bevacizumab addition to standard chemotherapy treatment in newly diagnosed advanced ovarian cancer demonstrated its efficacy. Bevacizumab monotherapy is effective in the treatment of persistent, resistant, or recurrent epithelial ovarian cancer (EOC). However, it remains unknown whether bevacizumab is effective for the clinical treatment of clear cell carcinoma (CCC). Some reports have suggested its efficacy in vitro and in vivo
	Vascular endothelial growth factor receptor	Sorafenib	[71]
Function	Sorafenib is a multikinase inhibitor of intracellular Raf kinases and cell surface kinase receptors and thereby inhibits tumor growth and angiogenesis
Efficacy	Phase I and II studies show limited clincial benefits of sorafenib in the treatment of EOC, both as monotherapy and in combination with other drugs. No data is available regarding its use in the treatment of clear cell carcinoma (CCC). However, it is regarded as a useful therapy for patients with renal CCC. Therefore, sorafenib may be efficacious in the treatment of CCC
	Vascular endothelial growth factor receptor	Pazopanib	[71]
Function	Pazopanib is a tyrosine kinase (multikinase) inhibitor that limits angiogensis and tumor growth by inhibiting cell surface vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors, and fibroblast growth factor receptors
Efficacy	Pazopanib monotherapy was relatively well tolerated, with similar toxicity to that of other small-molecule oral angiogenesis inhibitors. Promising single-agent activity was demonstrated in patients with recurrent ovarian cancer. Phase II and III trials indicate that pazopanib may have a role in the treatment of some women with EOC. No data demonstrates its efficacy in the treatment of CCC. However, pazopanib is regarded as useful in the treatment of renal CCC patients
Growth factor	Epidermal growth factor receptor	Gefitinib, erlotinib, and lapatinib	[78]
Function	Gefitinib is a tyrosine kinase inhibitor that inhibits numerous tyrosine kinases that are associated with transmembrane cell surface receptors on both normal and cancer cells, including the epidermal growth factor receptor (EGFR) assoicated tyrosine kinase
Efficacy	EGFR-targeted treatment had no effect when administered as monotherapy or as an adjunct to chemotherapy. However, EGFR-targeted treatment has shown promise in combination with other chemotherapeutic agents in clinical use. Further reports are expected. No data show the effects of targeting EGFR in CCC patients
	Human epidermal growth factor receptor 2	Trastuzumab	[79]
Function	Trastuzumab is a monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER 2) and mediates antibody-dependent cellular cytotoxicity by inhibiting the proliferation of cells that overexpress the HER 2 protein
Efficacy	HER-2 gene and protein overexpression have been reported in breast cancer and are associated with an aggressive clinical course and poor prognosis. A Gynecologic Oncology Group study demonstrated that HER 2 overexpression has no predictive or prognostic value in ovarian cancer. Although trastuzumab is not useful for ovarian cancer, no studies have investigated its use in the treatment of ovarian CCC. Further studies are needed to determine the efficacy of trastuzumab in the treatment of ovarian CCC
	Insulin-like growth factor type I receptor	AMG479	[80]
Function	A complete human monoclonal antibody against insulin-like growth factor type I receptor (IGF-1R)
Efficacy	IGF-1R inhibition with ganitumab was well tolerated and demonstrated modest single-agent activity in unselected patients with platinum-sensitive recurrent ovarian cancer. To our knowledge, two clinical trails have been completed, although the results have nto yet been published. There are no data pertaining to its use in the treatment of CCC
Tumor Marker	Cancer antigen 125	Oregovomab	[71]
Function	Oregovomab is a monoclonal antibody that binds to the antigen cancer antigen (CA 125)
Efficacy	A phase III clinical trial of intravenous oregovomab as post-chemotherapy consolidation has been conducted for EOC of tubal or peritoneal origin. Oregovomab monotherapy failed to improve outcomes after first line therapy. There are no data pertaining to its use in the treatment of CCC
Adhesion	α5β1 integrin	Volociximab	[81]
Function	Volociximab binds to and inhibits the activity of α5β1 integrin
Efficacy	A phase II, multicenter, single arm, two stage study evaluated the efficacy, safety, and tolerability of weekly administration of volociximab as a single agent for the treatment of platinum-resistant, advanced EOC and primary peritoneal cancer. Volociximab was well tolerated, but there is insufficient evidence of its efficacy. There are no reports of volociximab treatments for CCC
Signal	Mammalian target of rapamycin	Temsirolimus	[82]
Function	The mammalian target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate growth and homeostasis. Temsirolimus is an inhibitor of the mTOR pathway
Efficacy	Inhibitors of mTOR have shown therapeutic advantages when used in combination with other therapeutic modalities. Although clinical activity was low compared with the expected benefits, warranting further investigation. Existing data demonstrates the efficacy of targeting the mTOR pathway for CCC treatment in vitro and in vivo
	Src	Dasatinib	[71]
Function	Elevated activity of Src tyrosine kinase is suggested to be linked to cancer progression through the promotion of other signals. Dasatinib is a BCR-ABL tyrosine kinase inhibitor. It also inhibits the Src family, c-KIT, EPHA2, and platelet-derived growth factor receptor β
Efficacy	Dasatinib has minimal activity as a single agent in patients with recurrent EOC. There are no data pertaining to its use in the treatment of CCC
	c-Kit	Imatinib	[71]
Function	c-Kit is a receptor tyrosine kinase type III, which binds to stem cell factor, also known as “steel factor” or “c-kit ligand”. Signaling through c-kit plays a role in cell survival, proliferation, and differentiation
Efficacy	Some reports show dissapointing results in clinical outcomes. Few patients had sustained responses or stable disease, and treatment with imatinib did not prolong progression-free survival
DNA repair	Poly ADP ribose polymerase	Iniparib	[83]
Function	Proteins of the poly ADP ribose polymerase (PARP) family are involved in several cellular processes, mainly involving DNA repair and programmed cell death. Iniparib was originally believed to act as an irreversible inhibitor of PARP1
Efficacy	Phase II multicenter, single-arm clinical studies have been conducted to assess the efficacy and safety of carboplatin/gemcitabine in combination with iniparib in patients with platinum-sensitive or -resistant recurrent ovarian cancer. Phase III clinical trial of olaparib was initiated for patients with BRCA mutant ovarian cancer. However, low frequency of BRCA1/2 mutations in CCC were reported

ABL Abelson murine leukemia, BCR breakpoint cluster region, CA125 cancer antigen 125, EGFR epidermal growth factor receptor, EPHA2 ephrin type-A receptor 2, GFR growth factor receptor, HER2 human epidermal growth factor receptor 2, IGF-1R insulin like growth factor-1 receptor, mTOR mammalian target of rapamycin, PARP poly (ADP-ribose) polymerase, PDGFR platelet-derived growth factor receptor, VEGF vascular endothelial growth factor, VEGFR vascular endothelial growth factor receptor