title: Improving chemoradiation efficacy by PI3-K/AKT inhibition.
abstract: For many tumor types concurrent chemoradiation is the standard of care for locally advanced disease. Despite this intense treatment overall survival is still poor in various solid tumors. To improve outcome in these patients it is essential to develop new therapeutic strategies that enhance the efficacy of chemoradiation. The PI3-K/AKT pathway is often activated in solid tumors and is known to be an important tumor cell survival pathway. It is also well established that hypoxic tumor cells are resistant to both radiotherapy and chemotherapy. Evidence is emerging that activation of the PI3-K/AKT pathway affects the hypoxia tolerance of tumor cells and is involved in hypoxia-related treatment resistance. Already, the combination of concurrent chemoradiation and PI3-K/AKT inhibition has been explored in phase I studies in non-small cell lung, pancreatic and rectal cancer. This review summarizes the currently available literature concerning PI3-K/AKT signaling in relation to hypoxia and discusses the potential of PI3-K/AKT inhibition to overcome hypoxia-related treatment resistance to chemoradiation. Clinical studies testing the combination of chemoradiation and PI3-K/AKT inhibition and potential methods to predict treatment response are discussed.
authors.affiliation: Dept. of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Stegeman
authors.affiliation: Dept. of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Paul.Span@radboudumc.nl.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Span
authors.affiliation: Dept. of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Johannes H A M
authors.initials: JH
authors.lastname: Kaanders
authors.affiliation: Dept. of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Bussink
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D015687:Cell Hypoxia / Q000187:drug effects; D059248:Chemoradiotherapy / Q000379:methods*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt
keywords: Chemotherapy; HIF-1 signaling; Hypoxia; PI3-K/AKT inhibition; Radiotherapy