Abstract 238: NPAS3 is a novel late-stage acting progression factor in gliomas with tumor-suppressive functions

Abstract

Abstract Background: Primary brain tumors are among the top 5 causes of cancer-related deaths, with astrocytomas being the most common. Despite current therapies, patients with Glioblastoma multiforme (GBMs) (the most common sub-type of gliomas) unfortunately still succumb to a median survival of ∼ 1 year. In our effort to better comprehend the genetic basis of gliomas, we explored the prospects for new therapeutic targets. We previously cloned and characterized the function of NPAS3, a transcription factor which maps to human chromosome 14. Our principal aim is to comprehend the disease associations of NPAS3, since we recently identified expression in human astrocytes. We investigated NPAS3 as a candidate for astrocytomas based on findings archived from the Cancer Genome Project demonstrating a loss of NPAS3 expression and with loss-of-function deletions of human chromosome 14 with NPAS3 in 30-50% of astrocytomas. Methods-Results: After undertaking extensive functional analyses of NPAS3 using human surgical astrocytoma specimens, glioma cell line and human astrocyte cell line models, we now have novel and strong evidence supporting NPAS3 as an astrocytoma tumor suppressor involved in late-stage tumor progression. Our data in support of this discovery are based on: 1) Absent NPAS3 expression is predominant in high grade astrocytomas (79-83%), in comparison to low grade astrocytomas (29-35%) suggestive of an expression pattern typical of tumor suppressive- late stage progression factors. 2) Loss of function mutations (large deletions, frameshift, missense) of NPAS3, which are associated with a loss of heterozygosity of the NPAS3 locus are identified in GBMs. 3) Absent NPAS3 expression is predominant in >60% of malignant human glioma cell lines. 4) An over-expressed NPAS3 in malignant glioma cell lines suppresses the transformation potential, while the converse reduced expression promotes an increase in transformation potential. 5) A reduced NPAS3 expression (efficiency >90%) in concert with the human papillomavirus E6/E7 oncogenes, transforms a well characterized TERT immortalized human astrocyte cell line and promotes the growth of anaplastic astrocytomas, while an over-expressed NPAS3 suppresses the transformation. 6) NPAS3 mediates its tumor suppressive progression factor role in our glioma cell line and human astrocyte models by the control of cell cycle, proliferation and apoptosis. Conclusions: Our data provide compelling findings of NPAS3 as a novel gene involved in the cause of astrocytomas, with tumor suppressive and late-stage acting progression factor roles. We believe that this body of work is highly significant in our quest to better understand the biology of astrocytomas, and with prospects for improved targeted therapies in the treatment of this currently and relatively incurable disease. 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 238.