Citations

Abstract Biomarkers that select patients for therapeutics would benefit clinical trial design and patient care. The Akt pathway is a therapeutic target in Glioblastoma Multiforme (GBM) and an important determinant of patient outcome. However, it is not known whether activity of this pathway varies among GBM tumors. To investigate we used Akt pathway genes from published GBM expression datasets. We detected 5 patterns of Akt pathway gene expression and these Akt subgroups correlated with prognosis. We analyzed networks within subgroups using both gene set enrichment analysis and a novel method that scores relevance based on both expression and local network connectivity (Komurov et al., PLoS Comput Biol. 2010 6:8, 1-10). The results suggest therapeutic targets within the individual subgroups. Furthermore, preliminary analysis indicates that human GBM xenograft models and primary human GBM manifest similar Akt subgroups. We are investigating rodent xenograft models of Akt subgroups to evaluate subgroup-specific drug sensitivity, and will present a method and examples of analysis integrating gene expression data from human GBM xenografts and primary human GBM. We hypothesize that Akt subgroups will help personalize treatment for GBM therapeutics. Supported by Barrow Neurological Foundation, Halle Family Foundation, and NIH 1 K01 NS064952-01A1 (AMJ). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4138. doi:10.1158/1538-7445.AM2011-4138

Copper-zinc superoxide dismutase (Cu,ZnSOD) is the antioxidant enzyme that catalyzes the dismutation of superoxide (O 2 •− ) to O 2 and H 2 O 2 . In addition, Cu,ZnSOD also exhibits peroxidase activity in the presence of H 2 O 2 , leading to self-inactivation and formation of a potent enzyme-bound oxidant. We report in this study that lipid peroxidation of l -α-lecithin liposomes was enhanced greatly during the SOD/H 2 O 2 reaction in the presence of nitrite anion (NO 2 − ) with or without the metal ion chelator, diethylenetriaminepentacetic acid. The presence of NO 2 − also greatly enhanced α-tocopherol (α-TH) oxidation by SOD/H 2 O 2 in saturated 1,2-dilauroyl-sn-glycero-3-phosphatidylcholine liposomes. The major product identified by HPLC and UV-studies was α-tocopheryl quinone. When 1,2-diauroyl-sn-glycero-3-phosphatidylcholine liposomes containing γ-tocopherol (γ-TH) were incubated with SOD/H 2 O 2 /NO 2 − , the major product identified was 5-NO 2 -γ-TH. Nitrone spin traps significantly inhibited the formation of α-tocopheryl quinone and 5-NO 2 -γ-TH. NO 2 − inhibited H 2 O 2 -dependent inactivation of SOD. A proposed mechanism of this protection involves the oxidation of NO 2 − by an SOD-bound oxidant to the nitrogen dioxide radical ( • NO 2 ). In this study, we have shown a new mechanism of nitration catalyzed by the peroxidase activity of SOD. We conclude that NO 2 − is a suitable probe for investigating the peroxidase activity of familial Amyotrophic Lateral Sclerosis-linked SOD mutants.