ReviewCombination antiangiogenic therapy and radiation in head and neck cancers
Introduction
Head and neck squamous cell carcinoma (HNSCC), including cancers of the oral cavity, oropharynx, hypopharynx, pharynx and larynx, is the sixth most common cancer worldwide with approximately 600,000 new cases diagnosed each year [1]. The risk factors are tobacco and alcohol consumption [1], human papillomavirus (HPV) [2], [3], Epstein–Barr virus (EBV) [4], [5], areca nut [6], and dietary factors, like higher red meat consumption [1]. Two–third of patients are presented with advanced disease, and combined modality treatment with surgery, radiation therapy and chemotherapy is current standard of care [7]. Surgery can be performed if complete tumor resection is possible [8], however the majority of patients with advanced stage HNSCC are inoperable. The most frequent treatment is to combine chemotherapeutic agents with radiation [9]. Although concurrent chemo-radiation protocols are effective in treating HNSCC, treatment outcomes vary considerably and cytotoxicity side effects are significant [10]. In addition, tumor control and survival are still unsatisfactory. Even those who have achieved complete remission have a reported local recurrences incidence of 50–60%, and distant metastases develop in 20–30% of cases, with the 5-year overall survival rate less than 50% [11].
Recent studies have focused on the use of novel molecule-targeting agents as they have non-overlapping side effects and can be incorporated with existing treatment modality of HNSCC to improve outcome. Targeting epidermal growth factor receptor (EGFR) becomes a rational approach for HNSCC treatment since higher expression of EGFR has been associated with resistance to radiation and/or chemotherapy [8], [12]. Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), is an FDA-approved targeted agent for the treatment of advanced HNSCC [3], [13]. Combination of cetuximab and radiation improves the overall survival in patients with locally advanced HNSCC, compared to radiation alone (49 months versus 29.3 months, P = 0.03) [8], [14]. In order to provide personalized medicine and continue to improve outcome, other novel targeting strategies are needed. In the past 5 years, antiangiogenic therapies have seen a rapid ascent into mainstream clinical practice. Since angiogenesis is a hallmark of advanced and metastatic cancers, combining anti-angiogenic agents and radiation seems to be feasible, and warrants further investigation.
Section snippets
Vascular endothelial growth factor (VEGF) and its receptors: the role in HNSCC
VEGF plays a central role in the formation of new blood vessels and its importance in HNSCC has been well established [15]. The VEGF family of proteins consists of seven ligands, including VEGF A–E and placenta growth factor (PLGF) 1 and 2 [16]. PLGF, VEGF-A, VEGF-B are known to bind VEGFR-1. VEGF-A, VEGF-C and VEGF-D are known to bind VEGFR-2 [17], [18]. VEGF-C and VEGF-D also bind to VEGFR-3, which is expressed by lymphatic endothelial cells and hematopoietic progenitor cells [19], [20].
Radiation and hypoxia
Radiation-induced DNA double strand breaks trigger cell cycle arrest and cell death by apoptosis and/or necrosis. Oxygen is known to be a potent radiosensitizer that can promote reactive oxygen species (ROS)/free radicals production, essential for the induction of radiation-induced DNA damage [28]. As tumors grow, the microenvironment lacks an adequate blood supply, leading to regions that are underperfused and poorly oxygen ated or hypoxic [29]. This can lead to radiation resistance as a tumor
Antiangiogenic interactions and radiation
Antiangiogenic agents with radiation have been tested in experimental conditions with various tumor models, tumor host strains, starting tumor size, final tumor volume measured, and dosing and scheduling [40]. Tumor size can affect oxygen tension, nutrient supply, and pH, which are all factors in determining radiation response [38]. As tumor size increases, oxygen tension and pH decrease because of a greater demand for oxygen and nutrients, and glycolysis dominates, leading to acidosis [41]. A
Postulated mechanisms
The precise mechanism by which angiogenesis inhibition improves clinical outcome is not fully understood yet. On one hand, antiangiogenic agents traditionally are presumed to inhibit tumor vasculature formation, depriving the tumor of necessary nutrients and oxygen. Studies showed that the excess of EGF, VEGF and PDGF cause poor blood flow in disorganized and leaky tumor vessels, resulting in increased IFP, and poor drug delivery and hypoxia [45]. Data for head and neck cancer suggests that
Targeting angiogenesis agents combined with radiation on head and neck cancer
Antiangiogenic agents target the angiogenic process itself by inhibiting the action of factors that stimulate new blood vessel development [28], [38]. An overview of antiangiogenic agents combined with radiation is given in Table 1. A schematic diagram of antiangiogenic agents is also shown in Fig. 1.
Bevacizumab
Bevacizumab (Avastin), a recombinant anti-VEGFA monoclonal antibody, was approved by the US FDA for clinical use in 2004 with initial indication on colorectal cancer in combination with 5-fluorouracil-based conventional chemotherapy [49], [50], [51]. Now bevacizumab is approved for treatment of advanced colorectal cancer, non-small cell lung cancer, metastatic renal cell cancer, breast cancer, glioblastoma [52]. A recent phase II clinical trial using bevacizumab in combination with cetuximab in
Vandetanib
Vandetanib (ZD6474, Zactima) is a novel, orally available inhibitor of VEGFR-2 tyrosine kinase activity with additional activity against EGFR tyrosine kinase. A 2008 in vivo study, showed that the concurrent combination treatment of vandetanib and radiation is effective in both EGFR+ and EGFR- HNSCC tumor xenografts [60]. In EGFR+ tumors, vandetanib can inhibite PI3K/AKT signaling, while in EGFR- tumors, anti-VEGFR2 antitumor activity of vandetanib was obviously enhanced by radiation due to
Sunitinib
Sunitinib is a novel, multi-targeted, small molecule inhibitor of receptor tyrosine kinases (RTKs) that are involved in tumor proliferation and angiogenesis. Its inhibiting mechanism involves VEGFR-1, 2, and 3, PDGFR-α and -β, stem cell factor receptor (Kit) and fms-like tyrosine kinase 3 (Flt3) [27]. In a preclinical orthotopic xenograft model, neither sunitinib nor radiation therapy alone inhibited tumor proliferation and differentiation. When combining cetuximab and sunitinib, significant
Sorafenib
Sorafenib, is an oral inhibitor of the serine/threonine protein kinases B-Raf, C-Raf and also inhibits tyrosine kinase receptors like VEGFR-2, -3, PDGFR, Flt-3, and c-kit. It is currently being used to treat patients with advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and thyroid cancer [65], [66]. In a phase II trial, the efficacy and safety of single-agent sorafenib in patients with recurrent and/or metastatic head and neck squamous cell carcinoma and nasopharyngeal
Motesanib
Motesanib is a potent inhibitor of VEGFR-1, 2, and 3, PDGFR, and Kit receptors. In a preclinical study, motesanib inhibited tumor formation and endothelial cell angiogenic effects. Motesanib significantly improved intratumoral hypoxia and when combined with radiation, it can augment head and neck cancer killing effects in vitro and in vivo [71].
Linifanib (ABT-869)
Linifanib is a novel ATP-competitive receptor tyrosine kinase inhibitor of the VEGF and PDGF receptor family members. Previous studies showed that linifanib can inhibit PI3K/AKT, RAS/MAPK and STAT pathways in acute myeloid leukemia (AML) [72], [73], and in combination with mTOR inhibitors can Inhibit VEGF expression in several types of cancers [74], [75]. Our lab is currently working on the combination of linifanib with radiation on head and neck cancer cell lines. The preliminary data has
Prognostic factors/biomarkers
Hypoxia is a characteristic pathophysiological property of locally advanced solid tumors and such areas have been found in a wide range of human malignancies including cancers of the prostate, pancreas, rectum, breast, uterine cervix, brain tumors, malignant melanomas and head & neck cancer. Molecular studies investigating the tissue distribution of HIF-1α and of its target proteins CA-9 and GLUT-1 showed worse outcomes in cases exhibiting an overexpression of these endogenous markers [77], [78]
Conclusions
Despite recent advances in therapy for head and neck squamous cell carcinoma, chemotherapeutics cytotoxicity is of major concern. Novel therapy with targeted agents is a promising direction. Fig. 2 shows the possible advantages and mechanisms by using antiangiogenic therapies to enhance tumor response to radiation. There are some practical points needed to be considered as well. These agents theoretically should be used in combination with radiation or other chemo-therapies instead of single
Acknowledgment
This study was supported by Loma Linda University Cancer Center.
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