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Update on novel therapeutic agents for cervical cancer
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Gynecologic Oncology 110 (2008) S72 – S76 www.elsevier.com/locate/ygyno
Review
Update on novel therapeutic agents for cervical cancer ☆ Josep Maria del Campo a,⁎, Aleix Prat a , Antonio Gil-Moreno b , José Pérez a , Marta Parera a a
b
Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain Department of Gynecologic Oncology, Vall d'Hebron University Hospital, Barcelona, Spain Received 16 April 2008 Available online 9 June 2008
Abstract Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Cisplatin-based combination chemotherapy, the most commonly used cytotoxic therapy, has produced response rates ranging from 20% to 30% and overall survival of less than 10 months. Because of the minimal degree of success with cytotoxic therapies and the poor prognosis of patients with this disease, interest has increased in targeted therapeutics for the treatment of cervical cancer. In recent years, significant improvements in our understanding of the altered molecular events in tumor cells have led to the discovery of new targets and agents for clinical testing. Two of these promising targets are epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathway, which play critical roles in tumor growth and angiogenesis. Two monoclonal antibodies, cetuximab, which targets EGFR, and bevacizumab, which target the VEGF signaling pathway, are being evaluated as monotherapy and in combination with other agents and/or radiotherapy for the treatment of cervical cancer. In addition, VEGF receptor tyrosine kinase inhibitors, such as sorafenib and pazopanib, are being studied in phase I/II clinical trials. In this review, we discuss potential molecular targets and novel therapeutic strategies that are being investigated for the treatment of cervical cancer. © 2008 Elsevier Inc. All rights reserved. Keywords: Cervical cancer; EGFR; Cetuximab; Bevacizumab; Targeted therapy
Contents Introduction . . . . . . . . . . . . . . . Epidermal growth factor receptor type 1 Epidermal growth factor receptor type 2 Vascular endothelial growth factor. . . . Conclusions and future directions . . . . Conflict of interest statement . . . . . . References . . . . . . . . . . . . . . . .
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Introduction Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Cisplatin-based combination ☆
Presented at the First International Symposium on Cervical Cancer: Challenging Cervical Cancer, February 21-22, 2008, Madrid, Spain. ⁎ Corresponding author. Department of Medical Oncology, Vall d'Hebron University Hospital, Passeig de la Vall d'Hebron 119–129, 08035 Barcelona, Spain. Fax: +34 32746059. E-mail address: [email protected] (J.M. del Campo). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.04.016
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chemotherapy, the most commonly used cytotoxic therapy, has produced response rates ranging from 20% to 30% and overall survival of less than 10 months [1–4]. Because of the minimal degree of success with cytotoxic therapies for cervical cancer and the poor prognosis of patients with this disease, interest has increased in targeted therapeutics for the treatment of cervical cancer. In recent years, significant improvements in our understanding of the altered molecular events in tumor cells have led to the discovery of new targets and agents for clinical testing [5]. The role of targeted therapy for solid tumors is only
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beginning to be elucidated, but already there have been some successes. For example, the monoclonal antibody trastuzumab has been shown to inhibit tumor growth in breast cancer [6], and the monoclonal antibody bevacizumab has been shown to inhibit angiogenesis in breast cancer [7]. In this review, we will discuss potential molecular targets and novel therapeutic strategies that are being investigated for the treatment of cervical cancer. Epidermal growth factor receptor type 1 The epidermal growth factor (EGF) family of receptor tyrosine kinases comprises four different receptors: EGF type 1 (EGFR; also known as ErbB-1 and HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4) [8]. All proteins of this family possess an extracellular ligand-binding domain, a single hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase-containing domain. On endogenous ligandbinding to the extracellular domain, EGFR forms receptor homo- or heterodimers and activates the intrinsic tyrosine kinase-containing domain [9]. Subsequently, a complex network of signal transduction pathways that promote proliferation, motility, invasion, and angiogenesis is induced, including the phosphatidylinositol 3′-kinase/Akt/mTOR pathway and the Erk1/2 mitogen-activated protein kinase pathway [10]. EGFR has recently been identified as a promising target for cervical cancer [11]. This receptor is overexpressed in a variety of solid human malignancies, such as non-small cell lung cancer, colorectal cancer, and head and neck cancer. In patients with squamous cell carcinoma of the cervix, EGFR is overexpressed in up to 85% of cases, and EGFR expression has been associated with higher stage and poor prognosis [12– 17]. Moreover, EGFR has been shown to modulate tumor chemosensitivity and radiosensitivity. EGFR blockade with EGFR-blocking antibodies has synergistic effects with cisplatin or doxorubicin in human tumor xenografts in vivo [18–20]. In addition, radiotherapy increases the expression of EGFR in tumor cells, and blockade of EGFR signaling with EGFRblocking antibodies sensitizes cells to the effects of radiation [21]. Two strategies for targeting EGFR have met with success in the clinic [22]: monoclonal antibodies directed at the extracellular domain of the receptor (cetuximab, matuzumab, and panitumumab) and small-molecule, adenosine triphosphatecompetitive inhibitors of the receptor's tyrosine kinase (gefitinib and erlotinib). Cetuximab, a chimeric immunoglobulin G2 monoclonal antibody derived from the mouse monoclonal antibody 225 [23], has recently been approved for the treatment of squamous cell carcinoma of the head and neck in combination with radiotherapy and for the treatment of colorectal adenocarcinoma in combination with chemotherapy [24]. The addition of cetuximab to radiotherapy in the treatment of head and neck tumors resulted in a statistically significant prolongation in overall survival and improved locoregional control at 2 years [33]. In addition, cetuximab in combination with irinotecan increased response rates and progression-free survival in
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patients with colorectal cancer. These results provided a rationale for using anti-EGFR therapies as monotherapy or in combination with radiotherapy and/or chemotherapy for the treatment of cervical cancer. Preclinical models have shown an exquisite sensitivity of cervical cancer to cetuximab-mediated cellular cytotoxicity and to cetuximab-mediated inhibition of tumor growth [25]. Recently, monotherapy with matuzumab (800 mg/week), a humanized immunoglobulin G1 monoclonal anti-EGFR antibody, was reported to be effective in 44 patients with cervical cancer progressing after treatment with platinumbased chemotherapy [26]. Among 38 evaluated subjects, the best responses in the preliminary analysis were 2 partial responses and 9 cases of stable disease based on the investigators' criteria. The antibody was well tolerated. Several clinical studies of cetuximab for cervical cancer are ongoing, including a study evaluating the efficacy of cetuximab monotherapy in persistent or recurrent carcinoma of the cervix (Gynecologic Oncology Group [GOG]-0227E), a study evaluating the addition of cetuximab to radiotherapy for the treatment of early carcinoma of the cervix (GOG-9918), and a study of the addition of cetuximab to cisplatin for the treatment of persistent or recurrent carcinoma of the cervix (GOG-0076DD). EGFR tyrosine kinase inhibitors, such as gefitinib, erlotinib, and lapatinib, are being evaluated in cervical cancer. A multicenter phase II trial evaluated the clinical outcomes of gefitinib monotherapy (500 mg/day) as second- or third-line treatment in 30 patients with advanced squamous cell carcinoma or adenocarcinoma of the cervix [27]. Although there were no objective responses, 20% of patients experienced stable disease, and the median duration of stable disease was 111.5 days. Median time to progression was 37 days, and median overall survival was 107 days. Gefitinib was well tolerated: the most common drug-related adverse events were skin and gastrointestinal adverse events. Despite the lack of activity of gefitinib in this trial, another EGFR tyrosine kinase inhibitor, erlotinib, is being evaluated as monotherapy against persistent or recurrent squamous cell carcinoma of the cervix in a phase II clinical trial (GOG-0227D) and in combination with cisplatin and radiotherapy in locally advanced squamous cell cervical cancer (NCT00428194) [28]. Lapatinib, a dual tyrosine kinase inhibitor of HER1 and HER2, is being evaluated as monotherapy and in combination with pazopanib, a multitargeted tyrosine kinase inhibitor, in a phase II clinical trial in patients with International Federation of Gynecology and Obstetrics stage IVB or recurrent or persistent cervical cancer (VEG105281, see below). The results of these studies are eagerly awaited. Epidermal growth factor receptor type 2 HER2 is overexpressed or amplified in one fourth of breast cancer patients, and HER2 overexpression or amplification (HER2 positivity) is associated with a more aggressive clinical course [29]. However, the outcome of HER2-positive breast tumors has been markedly improved since the adoption of antiHER2 therapies, such as the monoclonal antibody trastuzumab [6,30–32].
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In cervical cancer, HER2 positivity has been reported in only 3% to 9% of cases and is more frequent in adenocarcinomas than squamous cell carcinomas [12,33]. In cervical cancer, in contrast to the situation with breast cancer, the prognostic value of HER2 positivity is controversial [34–38]. In one report, HER2 immunostaining was associated with poor survival in 126 patients with stage IB/IIA cervical carcinoma treated with radical hysterectomy and bilateral pelvic lymph node dissection [36]. In another report, HER2 positivity was a favorable prognostic factor in 55 patients with stage I–IVA cervical carcinoma treated with definitive radiotherapy [38]. These results suggest that there is little rationale for testing the efficacy of anti-HER2 monotherapies, such as trastuzumab, in the treatment of patients with cervical cancer. Vascular endothelial growth factor The dependence of tumor growth and metastasis on blood vessels makes angiogenesis one of the fundamental hallmarks of cancer [39] and a rational target for therapy [40]. One of the major pathways involved in angiogenesis is the vascular endothelial growth factor (VEGF) family of proteins and receptors. The VEGF pathway plays a crucial role in normal and pathologic angiogenesis, triggering multiple signaling networks that result in endothelial cell survival, migration, mitogenesis, differentiation, and vascular permeability [41]. Interestingly, VEGF expression is tightly controlled by oxygen tension, and hypoxia causes upregulation of VEGF gene expression in a manner similar to how hypoxia causes upregulation of erythropoietin expression [42]. The VEGF pathway is also upregulated by several growth factors, including EGF and EGFR [43]. The VEGF-related gene family of angiogenic and lymphangiogenic growth factors comprises 6 secreted proteins known as VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor (PlGF)-2. The primary effects of VEGF are mediated through binding to the VEGF receptors (VEGFRs): VEGFR-1, which binds VEGF-A, VEGF-B, and PlGF-1; VEGFR-2, which binds VEGF-A, VEGF-C, VEGF-D, and VEGF-E; VEGFR-3, which binds VEGF-C and VEGF-D and is expressed only in the lymphatic endothelium cells; and PIGF-2, which bind to Neuropilin-1. Once bound by VEGF, VEGFR-1 and VEGFR-2 dimerize, and the tyrosine kinase domain of each receptor “autophosphorylates” the other, leading to an active receptor that initiates multiple signaling cascades. Overexpression of VEGF has been associated with tumor progression and poor prognosis in several tumors, including cervical cancer [44]. For example, intratumoral protein levels of VEGF have been shown to be increased in cervical cancer compared to normal cervical tissue, and higher VEGF levels correlate with higher stage and increased risk of lymph nodes metastasis [45]. Other studies revealed that higher VEGF expression and increased tumor vascularization are independent predictors of poor disease-free and overall survival [38,46,47]. Furthermore, emerging data suggest that human papillomavirus, which is necessary for the establishment of invasive cervical carcinoma, may directly stimulate VEGF production through upregulation of the E6 oncoprotein [48,49].
The combination of bevacizumab, a humanized monoclonal antibody against VEGF-A, with chemotherapy significantly improved response rate and survival in patients with metastatic colorectal cancer and non-small cell lung cancer [50,51]. These findings validated inhibition of the VEGF signaling pathway as an important treatment modality in cancer. In 2006, a small retrospective study suggested encouraging antitumor activity of bevacizumab in combination with 5-fluorouracil in heavily pretreated patients with recurrent cervical cancer [52]. Since then, several phase II clinical trials of bevacizumab in cervical cancer have been initiated. One is evaluating the efficacy of bevacizumab monotherapy in persistent or recurrent squamous cell carcinoma of the cervix (GOG-0227C), another is investigating the efficacy of bevacizumab in combination with radiotherapy and cisplatin in untreated locally advanced cervical carcinoma (RTOG-0417), and yet another is evaluating the combination of bevacizumab with topotecan and cisplatin as first-line treatment for recurrent or persistent cervical cancer (GSK 107278). Recently, novel VEGFR tyrosine kinase inhibitors, such as sorafenib and pazopanib that have different ranges of nanomolar potency, selectivity, and pharmacokinetic properties are being studied as monotherapy and in combination with other therapies in phase I/II clinical trials for the treatment of cervical cancer. For example, sorafenib is being evaluated in a phase I/II clinical trial in combination with radiotherapy and cisplatin in patients with pathologically proven T1b-3bN0/1M0 carcinoma of the cervix (DDPDRO-002). Another study is being conducted to compare the efficacy and safety of pazopanib in combination with lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2, with that of lapatinib alone or pazopanib alone in subjects with metastatic cervical cancer (VEG105281). Signaling through the EGFR family may play an important role in the regulation of proangiogenic cytokines, and resistance to EGFR- and HER2-targeted therapies may be due to altered tumor angiogenesis. Targeting the EGFR and HER2 pathway with lapatinib and targeting the VEGF and platelet-derived growth factor pathway with pazopanib may overcome this resistance and provide therapeutic benefit. In addition, these studies will provide a great opportunity to identify biomarkers predictive of therapeutic response. Conclusions and future directions Currently, effective treatment options for advanced cervical cancer are limited. Improvements in our understanding of the altered molecular events in tumor cells have led to the discovery of promising new targets and agents for clinical testing in cancer, including cervical cancer. Two of these promising targets are EGFR and the VEGF signaling pathway, which play critical roles in tumor growth and angiogenesis. Cetuximab, which targets EGFR, and bevacizumab and VEGFR tyrosine kinase inhibitors, which target the VEGF signaling pathway, are being evaluated as monotherapy and in combination with other agents and/or radiotherapy for the treatment of cervical cancer. The results of these trials are eagerly awaited. However, targeting a single target has generally proved inadequate for the treatment of solid tumors. To individualize treatment, the
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multiple molecular abnormalities within tumor cell populations will need to be mapped out through molecular profiling. Molecular profiles will reveal putative molecular abnormalities in cervical cancer that may be appropriate for therapeutic modulation in the future. Conflict of interest statement The authors have no conflicts of interest to declare.
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Gynecologic Oncology 110 (2008) S72 – S76 www.elsevier.com/locate/ygyno
Review
Update on novel therapeutic agents for cervical cancer ☆ Josep Maria del Campo a,⁎, Aleix Prat a , Antonio Gil-Moreno b , José Pérez a , Marta Parera a a
b
Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain Department of Gynecologic Oncology, Vall d'Hebron University Hospital, Barcelona, Spain Received 16 April 2008 Available online 9 June 2008
Abstract Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Cisplatin-based combination chemotherapy, the most commonly used cytotoxic therapy, has produced response rates ranging from 20% to 30% and overall survival of less than 10 months. Because of the minimal degree of success with cytotoxic therapies and the poor prognosis of patients with this disease, interest has increased in targeted therapeutics for the treatment of cervical cancer. In recent years, significant improvements in our understanding of the altered molecular events in tumor cells have led to the discovery of new targets and agents for clinical testing. Two of these promising targets are epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathway, which play critical roles in tumor growth and angiogenesis. Two monoclonal antibodies, cetuximab, which targets EGFR, and bevacizumab, which target the VEGF signaling pathway, are being evaluated as monotherapy and in combination with other agents and/or radiotherapy for the treatment of cervical cancer. In addition, VEGF receptor tyrosine kinase inhibitors, such as sorafenib and pazopanib, are being studied in phase I/II clinical trials. In this review, we discuss potential molecular targets and novel therapeutic strategies that are being investigated for the treatment of cervical cancer. © 2008 Elsevier Inc. All rights reserved. Keywords: Cervical cancer; EGFR; Cetuximab; Bevacizumab; Targeted therapy
Contents Introduction . . . . . . . . . . . . . . . Epidermal growth factor receptor type 1 Epidermal growth factor receptor type 2 Vascular endothelial growth factor. . . . Conclusions and future directions . . . . Conflict of interest statement . . . . . . References . . . . . . . . . . . . . . . .
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Introduction Effective cytotoxic treatment options for advanced cervical cancer are exceedingly limited. Cisplatin-based combination ☆
Presented at the First International Symposium on Cervical Cancer: Challenging Cervical Cancer, February 21-22, 2008, Madrid, Spain. ⁎ Corresponding author. Department of Medical Oncology, Vall d'Hebron University Hospital, Passeig de la Vall d'Hebron 119–129, 08035 Barcelona, Spain. Fax: +34 32746059. E-mail address: [email protected] (J.M. del Campo). 0090-8258/$ - see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2008.04.016
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chemotherapy, the most commonly used cytotoxic therapy, has produced response rates ranging from 20% to 30% and overall survival of less than 10 months [1–4]. Because of the minimal degree of success with cytotoxic therapies for cervical cancer and the poor prognosis of patients with this disease, interest has increased in targeted therapeutics for the treatment of cervical cancer. In recent years, significant improvements in our understanding of the altered molecular events in tumor cells have led to the discovery of new targets and agents for clinical testing [5]. The role of targeted therapy for solid tumors is only
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beginning to be elucidated, but already there have been some successes. For example, the monoclonal antibody trastuzumab has been shown to inhibit tumor growth in breast cancer [6], and the monoclonal antibody bevacizumab has been shown to inhibit angiogenesis in breast cancer [7]. In this review, we will discuss potential molecular targets and novel therapeutic strategies that are being investigated for the treatment of cervical cancer. Epidermal growth factor receptor type 1 The epidermal growth factor (EGF) family of receptor tyrosine kinases comprises four different receptors: EGF type 1 (EGFR; also known as ErbB-1 and HER1), ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4) [8]. All proteins of this family possess an extracellular ligand-binding domain, a single hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase-containing domain. On endogenous ligandbinding to the extracellular domain, EGFR forms receptor homo- or heterodimers and activates the intrinsic tyrosine kinase-containing domain [9]. Subsequently, a complex network of signal transduction pathways that promote proliferation, motility, invasion, and angiogenesis is induced, including the phosphatidylinositol 3′-kinase/Akt/mTOR pathway and the Erk1/2 mitogen-activated protein kinase pathway [10]. EGFR has recently been identified as a promising target for cervical cancer [11]. This receptor is overexpressed in a variety of solid human malignancies, such as non-small cell lung cancer, colorectal cancer, and head and neck cancer. In patients with squamous cell carcinoma of the cervix, EGFR is overexpressed in up to 85% of cases, and EGFR expression has been associated with higher stage and poor prognosis [12– 17]. Moreover, EGFR has been shown to modulate tumor chemosensitivity and radiosensitivity. EGFR blockade with EGFR-blocking antibodies has synergistic effects with cisplatin or doxorubicin in human tumor xenografts in vivo [18–20]. In addition, radiotherapy increases the expression of EGFR in tumor cells, and blockade of EGFR signaling with EGFRblocking antibodies sensitizes cells to the effects of radiation [21]. Two strategies for targeting EGFR have met with success in the clinic [22]: monoclonal antibodies directed at the extracellular domain of the receptor (cetuximab, matuzumab, and panitumumab) and small-molecule, adenosine triphosphatecompetitive inhibitors of the receptor's tyrosine kinase (gefitinib and erlotinib). Cetuximab, a chimeric immunoglobulin G2 monoclonal antibody derived from the mouse monoclonal antibody 225 [23], has recently been approved for the treatment of squamous cell carcinoma of the head and neck in combination with radiotherapy and for the treatment of colorectal adenocarcinoma in combination with chemotherapy [24]. The addition of cetuximab to radiotherapy in the treatment of head and neck tumors resulted in a statistically significant prolongation in overall survival and improved locoregional control at 2 years [33]. In addition, cetuximab in combination with irinotecan increased response rates and progression-free survival in
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patients with colorectal cancer. These results provided a rationale for using anti-EGFR therapies as monotherapy or in combination with radiotherapy and/or chemotherapy for the treatment of cervical cancer. Preclinical models have shown an exquisite sensitivity of cervical cancer to cetuximab-mediated cellular cytotoxicity and to cetuximab-mediated inhibition of tumor growth [25]. Recently, monotherapy with matuzumab (800 mg/week), a humanized immunoglobulin G1 monoclonal anti-EGFR antibody, was reported to be effective in 44 patients with cervical cancer progressing after treatment with platinumbased chemotherapy [26]. Among 38 evaluated subjects, the best responses in the preliminary analysis were 2 partial responses and 9 cases of stable disease based on the investigators' criteria. The antibody was well tolerated. Several clinical studies of cetuximab for cervical cancer are ongoing, including a study evaluating the efficacy of cetuximab monotherapy in persistent or recurrent carcinoma of the cervix (Gynecologic Oncology Group [GOG]-0227E), a study evaluating the addition of cetuximab to radiotherapy for the treatment of early carcinoma of the cervix (GOG-9918), and a study of the addition of cetuximab to cisplatin for the treatment of persistent or recurrent carcinoma of the cervix (GOG-0076DD). EGFR tyrosine kinase inhibitors, such as gefitinib, erlotinib, and lapatinib, are being evaluated in cervical cancer. A multicenter phase II trial evaluated the clinical outcomes of gefitinib monotherapy (500 mg/day) as second- or third-line treatment in 30 patients with advanced squamous cell carcinoma or adenocarcinoma of the cervix [27]. Although there were no objective responses, 20% of patients experienced stable disease, and the median duration of stable disease was 111.5 days. Median time to progression was 37 days, and median overall survival was 107 days. Gefitinib was well tolerated: the most common drug-related adverse events were skin and gastrointestinal adverse events. Despite the lack of activity of gefitinib in this trial, another EGFR tyrosine kinase inhibitor, erlotinib, is being evaluated as monotherapy against persistent or recurrent squamous cell carcinoma of the cervix in a phase II clinical trial (GOG-0227D) and in combination with cisplatin and radiotherapy in locally advanced squamous cell cervical cancer (NCT00428194) [28]. Lapatinib, a dual tyrosine kinase inhibitor of HER1 and HER2, is being evaluated as monotherapy and in combination with pazopanib, a multitargeted tyrosine kinase inhibitor, in a phase II clinical trial in patients with International Federation of Gynecology and Obstetrics stage IVB or recurrent or persistent cervical cancer (VEG105281, see below). The results of these studies are eagerly awaited. Epidermal growth factor receptor type 2 HER2 is overexpressed or amplified in one fourth of breast cancer patients, and HER2 overexpression or amplification (HER2 positivity) is associated with a more aggressive clinical course [29]. However, the outcome of HER2-positive breast tumors has been markedly improved since the adoption of antiHER2 therapies, such as the monoclonal antibody trastuzumab [6,30–32].
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In cervical cancer, HER2 positivity has been reported in only 3% to 9% of cases and is more frequent in adenocarcinomas than squamous cell carcinomas [12,33]. In cervical cancer, in contrast to the situation with breast cancer, the prognostic value of HER2 positivity is controversial [34–38]. In one report, HER2 immunostaining was associated with poor survival in 126 patients with stage IB/IIA cervical carcinoma treated with radical hysterectomy and bilateral pelvic lymph node dissection [36]. In another report, HER2 positivity was a favorable prognostic factor in 55 patients with stage I–IVA cervical carcinoma treated with definitive radiotherapy [38]. These results suggest that there is little rationale for testing the efficacy of anti-HER2 monotherapies, such as trastuzumab, in the treatment of patients with cervical cancer. Vascular endothelial growth factor The dependence of tumor growth and metastasis on blood vessels makes angiogenesis one of the fundamental hallmarks of cancer [39] and a rational target for therapy [40]. One of the major pathways involved in angiogenesis is the vascular endothelial growth factor (VEGF) family of proteins and receptors. The VEGF pathway plays a crucial role in normal and pathologic angiogenesis, triggering multiple signaling networks that result in endothelial cell survival, migration, mitogenesis, differentiation, and vascular permeability [41]. Interestingly, VEGF expression is tightly controlled by oxygen tension, and hypoxia causes upregulation of VEGF gene expression in a manner similar to how hypoxia causes upregulation of erythropoietin expression [42]. The VEGF pathway is also upregulated by several growth factors, including EGF and EGFR [43]. The VEGF-related gene family of angiogenic and lymphangiogenic growth factors comprises 6 secreted proteins known as VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor (PlGF)-2. The primary effects of VEGF are mediated through binding to the VEGF receptors (VEGFRs): VEGFR-1, which binds VEGF-A, VEGF-B, and PlGF-1; VEGFR-2, which binds VEGF-A, VEGF-C, VEGF-D, and VEGF-E; VEGFR-3, which binds VEGF-C and VEGF-D and is expressed only in the lymphatic endothelium cells; and PIGF-2, which bind to Neuropilin-1. Once bound by VEGF, VEGFR-1 and VEGFR-2 dimerize, and the tyrosine kinase domain of each receptor “autophosphorylates” the other, leading to an active receptor that initiates multiple signaling cascades. Overexpression of VEGF has been associated with tumor progression and poor prognosis in several tumors, including cervical cancer [44]. For example, intratumoral protein levels of VEGF have been shown to be increased in cervical cancer compared to normal cervical tissue, and higher VEGF levels correlate with higher stage and increased risk of lymph nodes metastasis [45]. Other studies revealed that higher VEGF expression and increased tumor vascularization are independent predictors of poor disease-free and overall survival [38,46,47]. Furthermore, emerging data suggest that human papillomavirus, which is necessary for the establishment of invasive cervical carcinoma, may directly stimulate VEGF production through upregulation of the E6 oncoprotein [48,49].
The combination of bevacizumab, a humanized monoclonal antibody against VEGF-A, with chemotherapy significantly improved response rate and survival in patients with metastatic colorectal cancer and non-small cell lung cancer [50,51]. These findings validated inhibition of the VEGF signaling pathway as an important treatment modality in cancer. In 2006, a small retrospective study suggested encouraging antitumor activity of bevacizumab in combination with 5-fluorouracil in heavily pretreated patients with recurrent cervical cancer [52]. Since then, several phase II clinical trials of bevacizumab in cervical cancer have been initiated. One is evaluating the efficacy of bevacizumab monotherapy in persistent or recurrent squamous cell carcinoma of the cervix (GOG-0227C), another is investigating the efficacy of bevacizumab in combination with radiotherapy and cisplatin in untreated locally advanced cervical carcinoma (RTOG-0417), and yet another is evaluating the combination of bevacizumab with topotecan and cisplatin as first-line treatment for recurrent or persistent cervical cancer (GSK 107278). Recently, novel VEGFR tyrosine kinase inhibitors, such as sorafenib and pazopanib that have different ranges of nanomolar potency, selectivity, and pharmacokinetic properties are being studied as monotherapy and in combination with other therapies in phase I/II clinical trials for the treatment of cervical cancer. For example, sorafenib is being evaluated in a phase I/II clinical trial in combination with radiotherapy and cisplatin in patients with pathologically proven T1b-3bN0/1M0 carcinoma of the cervix (DDPDRO-002). Another study is being conducted to compare the efficacy and safety of pazopanib in combination with lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2, with that of lapatinib alone or pazopanib alone in subjects with metastatic cervical cancer (VEG105281). Signaling through the EGFR family may play an important role in the regulation of proangiogenic cytokines, and resistance to EGFR- and HER2-targeted therapies may be due to altered tumor angiogenesis. Targeting the EGFR and HER2 pathway with lapatinib and targeting the VEGF and platelet-derived growth factor pathway with pazopanib may overcome this resistance and provide therapeutic benefit. In addition, these studies will provide a great opportunity to identify biomarkers predictive of therapeutic response. Conclusions and future directions Currently, effective treatment options for advanced cervical cancer are limited. Improvements in our understanding of the altered molecular events in tumor cells have led to the discovery of promising new targets and agents for clinical testing in cancer, including cervical cancer. Two of these promising targets are EGFR and the VEGF signaling pathway, which play critical roles in tumor growth and angiogenesis. Cetuximab, which targets EGFR, and bevacizumab and VEGFR tyrosine kinase inhibitors, which target the VEGF signaling pathway, are being evaluated as monotherapy and in combination with other agents and/or radiotherapy for the treatment of cervical cancer. The results of these trials are eagerly awaited. However, targeting a single target has generally proved inadequate for the treatment of solid tumors. To individualize treatment, the
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multiple molecular abnormalities within tumor cell populations will need to be mapped out through molecular profiling. Molecular profiles will reveal putative molecular abnormalities in cervical cancer that may be appropriate for therapeutic modulation in the future. Conflict of interest statement The authors have no conflicts of interest to declare.
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