PATIENT-DERIVED XENOGRAFTS MIRROR THE PROTEOMIC PROFILE OF HUMAN GLIOBLASTOMA: IMPLICATIONS FOR PERSONALIZED DRUG DEVELOPMENT

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Abstract

BACKGROUND: (blind field). METHODS: Proteomic profiles of 20 patient-derived glioblastoma xenografts (PDGX), established and genetically characterized at Duke's Preston Robert Tisch Brain Tumor Center, were obtained using Reverse Phase Protein Arrays (RPPA). The proteomic profiles of the parent tumors, obtained from Duke's brain tumor repository, were also obtained using RPPA. The RPPA analysis examined the expression of 128 proteins and phosphoproteins in each primary tumor and PDGX. We compared the expression levels of the 128 proteins in each PDGX/primary tumor pair by plotting the expression level on the y-axis and name of the protein/phosphoprotein on the x-axis. RESULTS: For each primary tumor and PDGX pair, the expression of all but 4 to 8 proteins matched. These data indicate that PDGX retain the protemic profile of the parent tumor. Since the proteomic profile provides information on activated growth pathways, these data can be used to develop an arsenal of signal transduction modulators effective in arresting PDGX growth. For example, 5 xenografts exhibited high phosphorylation of EGFR and these PDGX also showed significantly increased phsophorylation of five other proteins, including GSK3-β, HER2, MAPK, Rb, and Src. Thus, a decrease in phosphorylation of these five proteins can be used to monitor the effectiveness of EGFR blockade in silencing EGFR signaling. If the agents found to be effective in silencing EGFR signaling also inhibit xenograft growth, then these agents can be further tested in glioblastoma patients whose tumors have similar molecular features. CONCLUSIONS: A concordance between the proteomic/phosphoproteomic profiles of PDGX and their parent tumor makes the PDGX an excellent preclinical model for personalized drug development. Acknowledgements: This research is supported by a grant from the NIH (R21NS078642) and a grant from the Musella Foundation to MMK. SECONDARY CATEGORY: Tumor Biology.

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