title: Combination antiangiogenic therapy and radiation in head and neck cancers.
abstract: Tumor angiogenesis is a hallmark of advanced cancers and promotes invasion and metastasis. Over 90% of head and neck squamous cell carcinomas (HNSCC) express angiogenic factors such as vascular endothelial growth factor (VEGF). Several preclinical studies support the prognostic implications of angiogenic markers for HNSCC and currently this is an attractive treatment target in solid tumors. Since radiotherapy is one of the most commonly used treatments for HNSCC, it is imperative to identify the interactions between antiangiogenic therapy and radiotherapy, and to develop combination therapy to improve clinical outcome. The mechanisms between antiangiogenic agents and ionizing radiation are complicated and involve many interactions between the vasculature, tumor stroma and tumor cells. The proliferation and metastasis of tumor cells rely on angiogenesis/blood vessel formation. Rapid growing tumors will cause hypoxia, which up-regulates tumor cell survival factors, such as hypoxia-inducing factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), giving rise to more tumor proliferation, angiogenesis and increased radioresistance. Thus, agents that target tumor vasculature and new tumor vessel formation can modulate the tumor microenvironment to improve tumor blood flow and oxygenation, leading to enhanced radiosensitivity. In this review, we discuss the mechanisms of how antiangiogenic therapies improve tumor response to radiation and data that support this combination strategy as a promising method for the treatment of HNSCC in the future.
authors.affiliation: Department of Pharmacology, Loma Linda University, Loma Linda, CA, USA; Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA; LLU Cancer Center Biospecimen Laboratory, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Heng-Wei
authors.initials: HW
authors.lastname: Hsu
authors.affiliation: Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA; Department of Biochemistry, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Wall
authors.affiliation: Division of Oncology & Hematology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Chung-Tsen
authors.initials: CT
authors.lastname: Hsueh
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Seungwon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ferris
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA, USA; LLU Cancer Center Biospecimen Laboratory, Loma Linda University, Loma Linda, CA, USA; Division of Oncology & Hematology, Loma Linda University, Loma Linda, CA, USA.
authors.forename: Chien-Shing
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Department of Medicine, Loma Linda University, Loma Linda, CA, USA; Department of Basic Sciences, Loma Linda University, Loma Linda, CA, USA; LLU Cancer Center Biospecimen Laboratory, Loma Linda University, Loma Linda, CA, USA. Electronic address: smirshahidi@llu.edu.
authors.forename: Saied
authors.initials: S
authors.lastname: Mirshahidi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans
chemical_list: D020533:Angiogenesis Inhibitors
keywords: 5-fluorouracil, hydroxyurea, radiotherapy; AA; AKT; Antiangiogenesis; CA; CCRT; CI; COX; Comibination therapy; DNA damage; EBV; EGF/R; ERCC; Epstein-Barr virus; FGF; FHX; FLK; FLT; GLUT; HIF; HNSCC; HPV; Head and neck cancer; IFP; IGRT; IMRT; KDR; Kit; MAPK; MMP; NPC; OSR; PDGF/R; PFR; PI3K; PLGF; RT; Radiation; STAT; TKI; Targeted therapy; VEGF/R; VEGFR/PDGFR inhibitor; X-ray repair cross-complementing protein; XRCC; antiangiogenic agent; carbonic anhydrase; concurrent chemoradiation; confidence interval; cyclooxygenase; epidermal growth factor/receptor; excision-repair cross-complementing protein; fetal liver kinase; fibroblast growth factor; fms-like tyrosine kinase; glucose transporter; head and neck squamous cell carcinoma; human papilloma virus; hypofractionated image-guided radiotherapy; hypoxia-inducing factor; intensity modulated radiotherapy; interstitial fluid pressure; kinase insert domain receptor; mTOR; mammalian target of rapamycin; matrix metalloproteinase; mitogen-activated protein kinase; nasopharyngeal carcinoma; overall survival rate; phosphoinositide 3-kinase; placenta growth factor; platelet-derived growth factor/receptor; progression free rate; protein kinase B; radiation; signal transducer and activator of transcription; stem cell factor receptor; tyrosine kinase inhibitor; vascular endothelial growth factor/receptor