Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy.
The tumor microenvironment, in particular, the tumor vasculature, as an important target for the cytotoxic effects of radiation therapy is an established paradigm for cancer therapy. We review the evidence that the phosphoinositide 3-kinase (PI3K)/Akt pathway is activated in endothelial cells exposed to ionizing radiation (IR) and is a molecular target for the development of novel radiation sensitizing agents. On the basis of this premise, several promising preclinical studies that targeted the inhibition of the PI3K/Akt activation as a potential method of sensitizing the tumor vasculature to the cytotoxic effects of IR have been conducted. An innovative strategy to guide cytotoxic therapy in tumors treated with radiation and PI3K/Akt inhibitors is presented. The evidence supports a need for further investigation of combined-modality therapy that involves radiation therapy and inhibitors of PI3K/Akt pathway as a promising strategy for improving the treatment of patients with cancer.
Kim
Dong Wook
DW
Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Nashville, TN 37232-9244, USA.
Huamani
Jessica
J
Fu
Allie
A
Hallahan
Dennis E
DE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000378:metabolism / Q000528:radiation effects; D004730:Endothelium, Vascular / Q000378:metabolism / Q000528:radiation effects*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000532:radiotherapy*; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000532:radiotherapy*; D000078183:Oxindoles; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000528:radiation effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011422:Propionates; D011758:Pyrroles / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D011836:Radiation Tolerance / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000502:physiology
D020533:Angiogenesis Inhibitors; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D016222:Fibroblast Growth Factor 2; D007211:Indoles; D000078183:Oxindoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011422:Propionates; D011758:Pyrroles; D011799:Quinazolines; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A; C489253:IC 486068; C412603:orantinib; C484760:PIK3CA protein, human