Ovarian Cancer Overview - Signaling Pathway. Diagnostics Marker. Targeted Therapy and Clinical Trials.

Fig.1 Ovarian cancer signaling pathway. Targeted agents (listed in orange boxes) include those in clinical use (colored in green) and those in preclinical or early phase development (colored in red) for the treatment of ovarian cancer.

An Introduction to Ovarian Cancer

Ovarian cancer is a type of cancer arising from the ovaries that are a part of the female reproductive system located at the side of the uterus. Ovaries can produce ova and the hormones estrogen and progesterone to maintain the normal physiological function. Ovarian cancer is caused due to abnormal cells invade or spread to other parts of the body. Symptoms often include abdominal bloating or swelling, quickly feeling full when eating, unexplained weight loss, discomfort in the pelvis area, changes in bowel habits and frequent urinate. To date, the specific cause of the ovarian cancer is unclear. Some risk factors include older age, inherited gene mutations especially the breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2), family history of ovarian cancer, estrogen hormone replacement therapy and age of menstruation started and ended. There are three main types of the cancer including the epithelial tumors that are the most percent of ovarian cancers, stromal tumors and the germ cell tumors. Currently, surgery, chemotherapy and targeted therapy are the major therapy approaches.

1 Main Signaling Pathways in Ovarian Cancer Therapy

1.1 HER2 (ErbB2) signaling cascade

Human epidermal growth factor receptor 2 (HER2) is a member of the family of epidermal growth factor receptors (EGFR) that consist of four members including EGFR1 or HER1, ErbB2 or HER2, HER3 and HER4. HER2 is over-expressed in numerous tumor types including breast, ovarian, colon, lung and cervical cancer. In ovarian cancer, HER2 is highly expressed in 25 and 30% cases. Several studies have revealed the correlation of HER2 overexpression with other prognostic factors, and HER2 overexpression is more frequently found in serous ovarian cancer, advanced stages, high age at diagnosis and differentiation. HER2 expression in ovarian cancer has been identified as a prognostic parameter, and some studies have shown a correlation between HER2 expression and survival. Inspired by the successful anti-HER2 treatment of breast cancer, much effort has been made to use HER2 as a potential target for epithelial ovarian cancer (EOC).

1.2 EGFR (HER1) signaling cascade

EGFR (HER1) is another member of the EGF family. Some growth factors, such as epidermal growth factor (EGF) and transforming growth factor alpha (TGFα), act as ligands of EGFR, which trigger dimerisation and phosphorylation, and then initiate downstream pathways, eventually leading to changes in gene expression required for cell proliferation and tumor growth. EGFR is overexpressed in ovarian cancer with up to 55-98% in EOC. EGFR overexpression often causes poor prognosis. In addition, the overexpression of EGFR can contribute to drug resistance. Study in germ line tumors showed that the high EGFR level can result in decreased drug sensitivity. Thus, EGFR has been regarded as a promising target for ovarian cancer therapy.

1.3 KIT, ABL and PDGFR signaling cascade

c-KIT, c-ABL and platelet derived growth factor receptor (PDGFR) are tyrosine kinases playing important roles in cell growth and proliferation and tumor progress. c-ABL is highly expressed in around 70% EOC cases. PDGFR-β and PDGFR-α are highly expressed in 81% and 13% ovarian cancer cases, repectively, and both are associated with high tumor grade. c-KIT has been found with overexpression level in 12-26% cases, also in association with higher grade.

1.4 VEGFR signaling cascade

The vascular endothelial growth factor (VEGF) pathway is one of the key regulators associated with various biology functions. The VEGF/VEGF-receptor axis comprises multiple ligands and receptors. Activation of the VEGF-receptor pathway can lead to a network of signaling processes that promote endothelial cell growth, migration, and survival from pre-existing vasculature. The VEGF family plays a critical role in promoting tumor angiogenesis and in pathogenesis of several human cancers, which has led to the rational design and development of agents that selectively target this pathway. The effects of the ligands are mediated through tyrosine-kinase receptors (VEGFR), which are considered as novel targets for the treatment of EOC.

Ovarian Cancer Diagnosis

2.1 Molecular Markers for Ovarian Cancer

Most of ovarian cancer patients are diagnosed with late stage disease due to the lack of distinctive symptoms and reliable biomarkers. Besides, at diagnosis, about half the tumors are intrinsically resistant to chemotherapy, and up to half of the tumors initially responsive will develop resistance. Therefore, identification of molecular markers in early detection is useful and has a significant impact on cancer survival. Moreover, the existence of markers that would be predictive of outcome may allow for improved and more targeted therapy.

Currently, screening methods focusing on identifying mutations and abnormalities in BRCA1 and BRCA2 genes have been extensively used in current clinical practice. Women often have obviously increased risks in developing ovarian cancer with mutations in these tumor suppressor genes. Ras Homologue Member 1 (ARHI) located on chromosome 1p31 is a tumor suppressor gene presenting in roughly 40% of ovarian carcinoma. Normally, the expression of ARHI is in normal ovarian epithelial cells, which will be lost upon the formation of ovarian cancer. Other molecular markers used in ovarian cancer diagnosis include opioid binding protein/cell adhesion molecule-like gene (OPCML), RAS association domain family 1A gene (RASSF1A), insulin-like growth factor binding protein 3 (IGFBP-3), 14-3-3sigma (SFN), etc.

2.2 Protein Markers for Ovarian Cancer

Currently, the only biomarker that has proven to detect ovarian cancer before the onset of clinical symptoms and is widely used in clinical practice is CA125. It is a high-molecular-weight glycoprotein normally expressed in a variety of epithelial cell types. CA125 is regarded as one of the highest sensitivity and specificity among biomarkers for ovarian cancer. Haptoglobin is an acute phase reactant protein that originates mainly from the liver, which has been shown to be expressed in some forms of ovarian cancer. Concentration of this marker is significantly elevated during late stages of ovarian cancer, suggesting it is important marker in diagnosing. Human Epididymis Protein 4 (HE4) as a component of the disulfide-core protein group, it is also elevated in ovarian cancer. In comparison to CA125, SMRP, CA72-4, and osteopontin, HE4 has the highest sensitivity in detecting stage I ovarian cancer. Mesothelin is a protein highly expressed in several cancers such as mesotheliomas, ovarian, and pancreatic cancers, which has been confirmed to be a useful diagnostic marker. Mesothelin has very high specificity and sensitivity for patients with ovarian cancer. Other protein markers include B7-H4, Prostasin, Macrophage Colony Stimulating Factor and OVX1, and VEGF.

3 Targeted Therapy for Ovarian Cancer

Various molecular mechanisms involved in the pathogenesis of ovarian cancer provide promising ways for targeted therapy. Major components of cell signaling pathways, such as the HER2, EGFR, KIT, ABL and PDGFR, and VEGFR, are altered in ovarian cancer cells by oncogenes through overexpression or mutation, leading to dysregulated cell signaling and cell proliferation. Here, we summarize the potential targets and new drugs developed that have been used in recent, ongoing and future clinical trials to try to improve the clinical outcomes of this disease (Table1-6).

3.1 Ovarian cancer therapy for HER2 pathway

Monoclonal antibody pertuzumab (2C4) represents a novel approach targeting HER2 to treat ovarian cancer. Pertuzumab binds to the extracellular domain II of HER2 and inhibits the dimerisation of HER2 with other HER receptors. In preclinical study, Pertuzumab showed its significant inhibition activity to OVCA433 ovarian carcinoma cells, and can interfere the HER signaling pathway to inhibit tumor growth. A Phase I clinical trial has evaluated the safety and pharmacokinetics of pertuzumab in patients with incurable, locally advanced, recurrent or metastatic solid carcinoma. Trastuzumab is another monoclonal antibody against HER2, which has been used in treatment of HER2 positive breast cancer. It is also evaluated in Phase II clinical trial to treat ovarian cancer.

Table 1 Clinical trials of HER2 inhibitor pertuzumab

According to statistics, a total of 2 pertuzumab projects targeting ovarian cancer HER2 are currently in clinical stage and both are recruiting.

Table 2 Clinical trials of HER2 inhibitor Trastuzumab

According to statistics, a total of 5 Trastuzumab projects targeting ovarian cancer HER2 are currently in clinical stage, of which 3 are recruiting and 2 are not recruiting.

3.2 Ovarian cancer therapy for EGFR (HER1) pathway

Gefitinib (ZD1839) is a selective EGFR tyrosine kinase inhibitor by blocking EGFR downstream signaling pathways and to induce cell cycle arrest. It also can inhibit angiogenesis by decreasing expression of angiogenetic growth factors. Gefitinib has been performed in a clinical Phase I to evaluate safety, pharmacodynamic and pharmacokinetic trial in patients with five selected solid tumor types including ovarian cancer. Subsequently, a clinical Phase II trial to assess activity and toxicity of gefitinib in patients with EOC has been completed. Gefitinib combined with the anti-estrogen tamoxifen in ovarian cancer refractory or resistant to platinum- and taxane-based therapy in a clinical Phase II trial, and showed an obvious tumor inhibition effect. Cetuximab is a monoclonal antibody against the external domain of EGFR to block ligand binding and receptor activation. Cetuximab together with benzoporphyrin derivate monoacid-A based photodynamic therapy can significantly inhibit tumor cell proliferation and improve survival in a model of metastatic ovarian cancer, suggesting it can be a potential additional agent in chemotherapy of ovarian cancer. Other EGFR inhibitors include Erlotinib (OSI-774) and Lapatinib (GW572016).

Table 3 Clinical trials of EGFR tyrosine kinase inhibitor Gefitinib

According to statistics, a total of 1 Gefitinib project targeting ovarian cancer EGFR tyrosine kinase is currently in clinical stage and is not recruiting.

Table 4 Clinical trials of EGFR inhibitor Cetuximab

According to statistics, a total of 2 Cetuximab projects targeting ovarian cancer EGFR are currently in clinical stage, of which 1 is recruiting and 1 is not recruiting.

3.3 Ovarian cancer therapy for KIT, ABL and PDGFR pathway

Imatinib (STI571) is a potent inhibitor of c-KIT, c-ABL and PDGFR. It can inhibit cell growth of three primary ovarian cultures and two immortalized cultures, all PDGFR-positive. In a preclinical trial, treated with imatinib or combined with other drug, and results showed combination treatment significantly reduced tumor weight in all three human ovarian cancer cell lines. A clinical Phase II trial of imatinib in combination with docetaxel in patients with c-KIT- or PDGFR-positive platinum-resistant recurrent EOC, results showed that the combination therapy was well tolerated.

3.4 Ovarian cancer therapy for VEGFR pathway

Bevacizumab is a humanized recombinant monoclonal antibody that inhibits VEGFR pathway. To date, there are several clinical trials have evaluated the effect of bevacizumab in the treatment of ovarian cancer. These clinical results showed distinct tumor-killing activity in patients with ovarian cancer. Vatalanib (PTK787) is another potent inhibitor of VEGFR that has shown promising activity in patients with metastatic colorectal cancer, lung and breast cancer. It was examined in a clinical Phase Ib trial of vatalanib in combination with paclitaxel and carboplatin as first line therapy in stage IC-IV EOC. Other VEGFR inhibitors include Sorafenib, Pazopanib, SU6668, AEE788 and semaxanib (SU5416).

Table 5 Clinical trials of VEGFR pathway inhibitor Bevacizumab

According to statistics, a total of 70 Bevacizumab projects targeting ovarian cancer EGFR are currently in clinical stage, of which 30 are recruiting and 40 are not recruiting.

Table 6 Clinical trials of VEGFR inhibitor Pazopanib

According to statistics, a total of 4 Pazopanib projects targeting ovarian cancer EGFR are currently in clinical stage and are not recruiting.