title: Dual inhibition of the PI3K/mTOR pathway increases tumor radiosensitivity by normalizing tumor vasculature.
abstract: The aberrant vascular architecture of solid tumors results in hypoxia that limits the efficacy of radiotherapy. Vascular normalization using antiangiogenic agents has been proposed as a means to improve radiation therapy by enhancing tumor oxygenation, but only short-lived effects for this strategy have been reported so far. Here, we show that NVP-BEZ235, a dual inhibitor of phosphoinositide-3-kinase (PI3K) and mTOR, can improve tumor oxygenation and vascular structure over a prolonged period that achieves the aim of effective vascular normalization. Because PI3K inhibition can radiosensitize tumor cells themselves, our experimental design explicitly distinguished effects on the blood vasculature versus tumor cells. Drug administration coincident with radiation enhanced the delay in tumor growth without changing tumor oxygenation, establishing that radiosensitization is a component of the response. However, the enhanced growth delay was substantially greater after induction of vascular normalization, meaning that this treatment enhanced the tumoral radioresponse. Importantly, changes in vascular morphology persisted throughout the entire course of the experiment. Our findings indicated that targeting the PI3K/mTOR pathway can modulate the tumor microenvironment to induce a prolonged normalization of blood vessels. The substantial therapeutic gain observed after combination of NVP-BEZ235 with irradiation has conceptual implications for cancer therapy and could be of broad translational importance.
authors: Gray Institute for Radiation Oncology and Biology, Oxford University, Oxford, United Kingdom.
authors: Emmanouil
authors: E
authors: Fokas
authors: Jae Hong
authors: JH
authors: Im
authors: Sally
authors: S
authors: Hill
authors: Sabira
authors: S
authors: Yameen
authors: Michael
authors: M
authors: Stratford
authors: John
authors: J
authors: Beech
authors: Wolfgang
authors: W
authors: Hackl
authors: Sauveur-Michel
authors: SM
authors: Maira
authors: Eric J
authors: EJ
authors: Bernhard
authors: W Gillies
authors: WG
authors: McKenna
authors: Ruth J
authors: RJ
authors: Muschel
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011836:Radiation Tolerance; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases