Abstract 3226: Targeting PI3K signaling in a xenograft model of nasopharyngeal carcinoma

Abstract

Abstract Nasopharyngeal carcinoma (NPC) is a cancer of the head and neck and is particularly common in Southern China and parts of the developing world. NPC may be a significant world health problem since it is likely to be underreported in parts of Southeast Asia and North Africa. The nonkeratinizing forms of nasopharyngeal carcinoma are divided into two subtypes based on histology (“differentiated” WHO type II and “undifferentiated” WHO type III.) Our analysis of gene expression data from an Affymetrix study of type II and type III NPC tumor biopsies using the Connectivity Map, a bioinformatics algorithm developed at the Broad Institute, suggests that the PI3K-Akt-mTOR pathway may be more highly activated in NPC type III. The array data may also reflect differential sensitivity to PI3K-Akt-mTOR pathway inhibitors and that the underlying genetic lesions that drive Akt activity in NPC type II and NPC type III are different. In addition, analysis using an algorithm that analyzes sets of functionally related genes, Gene Set Enrichment Analysis (GSEA), revealed that in NPC type III tumors, there is an increased expression of genes associated with epithelial-mesenchymal transition (EMT); a developmental program characterized by loss of cell adhesion, repression of E-cadherin expression and increased cell mobility. EMT has been reported to be a feature of several metastatic cancers. We performed biochemical assays in vitro on NPC cells that supported these findings, and then developed a xenograft tumor model that replicates invasive and metastatic NPC in immunodeficient mice. This model allows us to track tumor development by bioluminescence non-invasively over time. Blocking the PI3K-Akt-mTOR signaling pathway with Rapamycin, an mTOR inhibitor, had a significant effect on the growth of metastases. Taken together, this suggests that the activation of the PI3K-Akt-mTOR pathway and EMT in NPC type III tumors may provide a molecular basis for the distinction between NPC type II and NPC type III, and that the type III phenotype is associated with metastatic progression in nasopharyngeal carcinoma. It may also provide prognostic and therapeutic implications for more efficacious treatment specifically targeting metastasis in NPC. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3226.