Abstract B15: Mapping topology of PI3K/AKT/mTOR signaling in glioblastoma molecular subgroups

Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features and mapped their PI3K/AKT pathway topology. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Evidence indicates one subtype is very sensitive to BCNU or CCNU. A key question is whether oncogene drivers differ in subgroups. We developed a new method to map topology of oncogene signaling in vivo using TCGA reverse phase protein array data. Our evidence indicates topology of PI3K/AKT/mTOR signaling varies between subgroups suggesting sensitivity to pathway inhibitors will differ. AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subgroups will help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets. Note: This abstract was not presented at the conference. Citation Format: Anna Joy, Archana Ramesh, Ivan Smirnov, Mark Reiser, Gorden Mills, Seungchan Kim, Burt Feuerstein. Mapping topology of PI3K/AKT/mTOR signaling in glioblastoma molecular subgroups. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B15.