Table 3 Examples of targeted molecular cancer therapeutics for epithelial ovarian cancer

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