ErbB Receptors and ErbB Targeted Therapies in Endometrial Cancer

The Epidermal Growth Factor system is present in human organs and plays an 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. Dysregulation of the Epidermal Growth Factor signaling network is implicated in the pathogenesis of various disorders. Especially in cancer, the Epidermal Growth Factor system becomes hyperactivated with various mechanisms (ligand overproduction, receptor overproduction, constitutive receptor activation). EGFR overexpression may have a dual role in endometrial cancer. It seems that in type I endometrial cancer, EGFR overexpression did not affect disease progression. However in type II endometrial cancer, EGFR overexpression associated with high grade disease 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: anti-ErbB monoclonal antibodies (MoAbs) and ErbB-specific tyrosine kinase inhibitors (TKIs). ErbB targeted therapies have still shown modest effect in unselected endometrial cancer patients. However, they may be clinically active as adjuvant therapy in well-defined subgroups of type II endometrial cancer patients with EGFR and ErbB-2 overexpression.


Introduction
Endometrial cancer (EC) is the most common malignancy of the female genital tract and occurs primarily in postmenopausal women [1] [2].Overall, about 2.64% of women develop EC during their lifetime [1].
The epidermal growth factor system (EGF system) is present in human organs and plays an important role in cell proliferation, differentiation and apoptosis during embryogenesis and postnatal development [3] [4].
Dysregulation of the EGF signaling network is implicated in various disorders [3] [5].Especially in cancer, the EGF system contributes in proliferation, transformation, angiogenesis, migration and invasion [6].
ErbB receptors belong to subclass I of the superfamily of Receptor Tyrosine Kinases (RTKs) [3] [6].They are trans-membrane glycoproteins with an extracellular region containing two ligand-binding domains, an extracellular juxtamembrane region, a hydrophobic transmembrane domain and an intracellular domain with tyrosine kinase activity [7] [8].ErbB receptors catalyze the transfer of the γ phosphate of ATP to hydroxyl groups of tyrosines in target proteins [9].Moreover, EGF system has numerous ligands.According to their affinity for one or more ErbB receptors, the ligands divided into: 1) Ligands with binding specificity for EGFR: EGF, transforming growth factor-a (TGF-a) and amphiregulin (AR) [6] [7] [10].
The ligands for ErbB receptors bind to the extracellular domain, resulting in receptor activation by homodimer and/or heterodimer formation and the subsequent transphosphorylation of tyrosine residues in the cytoplasmic region [6] [7] [13].However, there is no direct ligand for ErbB-2 receptor [6].
Ligand binding stabilizes extracellular region in the open conformation and leads to the formation of both homodimeric and heterodimeric ErbB receptor complexes [8] [15]- [17].The dimeric formation triggers receptor activation by an allosteric mechanism [18].That leads to intracellular kinase activation and initiation of downstream signaling pathways [7] [17] [19].
The dimerization of ErbB receptors represents the fundamental mechanism that drives transformation [24].Although both homodimerization and heterodimerization result in activation of the EGF signaling network, heterodimers are more potent and mitogenic [5].

Dysregulation and Oncogenesis
Dysregulation of the EGF signaling network is implicated in cancer, diabetes, autoimmune, inflammatory, cardiovascular and nervous system disorders [3] [5].
Loss of control of the cell functions mediated by the EGF signaling network is a hallmark of oncogenesis, in which the balance between cell proliferation and differentiation is disturbed.Several types of human cancer associated with dysregulation of the EGF signaling network [3].

Classification
EC is the most common malignancy of the female genital tract [1].Based on clinical and pathological features, sporadic EC is classified into 2 types [49] [50].

Expression and Clinical Significance of ErbB Receptors
Due to the inactive status of postmenopausal endometrium, it is expectable to find significantly higher expression of the ErbB receptors in EC tissue [55].
In endometrium, EGFR localized to the basal part of surface epithelial cells, only in stromal cells, or both to epithelial and stromal cells [56]- [65].It is primarily located to the cell membrane but also located to the cytoplasm [55] [61]- [69].
EGFR over expression may have a dual role in EC [71].It seems that in type I EC, EGFR overexpression did not affect disease progression [71].However in type II endometrial cancer, EGFR overexpression associated with high grade disease and adverse clinical outcome [63] [64] [71].

Classification
EGFR and ErbB-2 as targets for cancer therapy have been investigated for over 30 years [85].There are 2 major classes of ErbB targeted therapies: [85] [86].
2) EGFR and ErbB-2 TKI (lapatinib) block the binding of ATP to the intracellular domain of EGFR and ErbB-2 and prevents tyrosine kinase activity and subsequent intracellular signaling [85] [86].

Anti-ErbB Monoclonal Antibodies (MoAbs) in Endometrial Cancer
Anti-ErbB-2 MoAb (trastuzumab) may be an attractive and viable therapeutic option in patients with advanced, recurrent and/or metastatic EC overexpressing ErbB-2 [87].
Clinical responses to trastuzumab as single agent or in combination with chemotherapy have been reported in several case reports [87]- [90].
However a phase II study of trastuzumab as single agent in unselected patients with advanced or recurrent EC overexpressing ErbB-2, failed to demonstrate significant activity [91].
Moreover a phase II study of carboplatin/paclitaxel with or without trastuzumab in patients with advanced or recurrent type II EC (papillary serous) overexpressing ErbB-2, is currently underway (NCT01367002) [92].
However a phase II study of gefitinib as single agent in unselected patients with persistent or recurrent EC overexpressing EGFR, demonstrate 4.1% complete response rate and 16.6% progression free survival ≥6 months [93].
Also a phase II study of erlotinib as single agent in unselected patients with metastatic or recurrent EC, demonstrate 12.5% partial response rate [94].
Moreover a phase II study of lapatinib as single agent in unselected patients with persistent or recurrent EC, demonstrate 3.3% partial response rate and 10% progression free survival ≥6 months [95].

Effectiveness in Well-Defined Subgroups of Endometrial Cancer Patients
Recent years, molecular targeted therapies have still shown modest effect in unselected EC patients [96].Overall response rate to these drugs is modest, unless they are associated with chemotherapy or radiotherapy [85].ErbB targeted therapies have not clinically tested in type II EC [71].Perhaps they may be clinically active as adjuvant therapy in well-defined subgroups of type II EC patients with EGFR and ErbB-2 overexpression [64] [65] [71] [87]- [89] [97]- [104].