ErbB Targeted Therapy in Endometrial Cancer

The Epidermal Growth Factor system is present in human organs and play important role in cell proliferation, differentiation and apoptosis during embryogenesis and postnatal development. It has four receptors (EGFR, ErbB-2, ErbB-3 and ErbB-4) and numerous ligands. ErbB receptors are trans-membrane glycoproteins. Their dimerization leads to intracellular kinase activation. As a result, a number of tyrosine residues in the COOH-terminal portion of ErbB receptors become phosphorylated. Those phosphorylated tyrosine residues function as docking sites for cytoplasmic proteins. Recruitment of proteins initiates intracellular signaling via several pathways: 1. Ras / Raf / mitogen-activated protein kinase (MAPK) pathway (regulates cell proliferation and survival). 2. Phosphatidylinositol 3-kinase (PI3K) / Akt pathway (regulates cell growth, apoptosis, tumor invasion, migration and resistance to chemotherapy). 3. Signal transducers and activators of transcription (STAT) pathway (regulates oncogenesis and tumor progression). 4. Src Kinase pathway (regulates cell proliferation, migration, adhesion, angiogenesis and immune function). 5. Phospholipase Cγ / protein kinase C pathway. Dysregulation of the Epidermal Growth Factor system signaling network, is implicated in the pathogenesis of various disorders. Especially in cancer, it becomes hyperactivated with various mechanisms (ligand overproduction, receptor overproduction, constitutive receptor activation). It is also contributes in proliferation, transformation, angiogenesis, migration and invasion. During menstrual cycle, ErbB receptors have different levels in normal endometrium. Moreover due to the inactive status of postmenopausal endometrium, it is expectable to find significantly higher expression of the 4 ErbB receptors in endometrial cancer tissue. Especially in patients with type II endometrial cancer (papillary serous or clear cell), there are high expression levels of ErbB receptors. Among them, many patients with dismal outcome are positive for all ErbB receptors. EGFR overexpression in type I endometrial cancer, did not affect disease progression. However EGFR overexpression in type II endometrial cancer, associated with high grade and adverse clinical outcome. Moreover ΕrbB-2 overexpression, especially in type II endometrial cancer, is an indicator of a highly aggressive disease with poor overall survival. The potential role of ErbB receptors (especially EGFR and ErbB-2) as targets for cancer therapy has been investigated for over 20 years. There are 2 major classes of ErbB targeted therapies: 1. anti-ErbB monoclonal antibodies (MoAbs): Anti-EGFR MoAbs bind to the extracellular domain of EGFR and prevent ligand binding and ligand dependent receptor activation. Anti-ErbB-2 MoAb binds to the extracellular domain of ErbB-2 and interferes with ligand independent receptor activation. 2. ErbB-specific tyrosine kinase inhibitors (TKIs): TKIs block the binding of ATP to the intracellular domain of EGFR and/or ErbB-2 and blocks ErbB activity and subsequent intracellular signaling. The overall response rate to ErbB targeted therapies is modest, unless they are associated with chemotherapy or radiotherapy. Moreover molecular targeted therapies have still shown modest effect, in unselected endometrial cancer patients. However, preclinical data suggest that ErbB targeted therapies may be clinically active as adjuvant therapy, in well-defined subgroups of type II endometrial cancer patients with EGFR and ErbB-2 overexpression.