In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3347-3347
Abstract:
The Cancer Genome Atlas Network described genomic abnormalities and gene expression-based molecular subtypes of GBM that showed a strong relationship between subtypes, genomic alterations and different neural lineages. Future studies are required to elucidate the intricate relationship between tumor subtypes and treatment response. We have thus embarked on a comprehensive effort to detecting expression signatures that are associated with response to the therapy and these signatures may allow prospective selection of patients with high likelihood of responding to therapy. Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes including cell fate decision, differentiation, proliferation, survival, angiogenesis and migration. Recent studies indicate that the Notch signaling pathway regulates normal stem cells in the brain, and glioma stem Cells (GSCs) with high Notch activity. We investigated the effects of Notch pathway inhibition on GSCs growth using commercially available inhibitors. Drug cytotoxicity test on 16 GSCs show differential growth response to Notch inhibitors stratifying GSCs into two groups: responders (6 cell lines) vs non-responders (10 cell lines). Gene expression clustering identified a responder gene signature enriched in 1: proneural genes such as Olig2, Sox-9, NKX2-2, and 2: Notch signaling component such as Notch-1, Notch-3, Hes-3 and Hes-5. These signature were validated by western blot analysis. Treatment with Notch inhibitors reduced neurosphere formation in vitro accompanied with attenuated Notch intracellular domain (NICD), Hes-1, Hes-3, and Hes-5. In addition, the expression of nestin-the stem cell marker was reduced and an increased expression of lineage differentiation markers TuJ1 and GFAP was observed following Notch inhibition. In conclusion, we have identified a responder signature for a group of glioma stem cells that can be targeted by Notch inhibitors and this may allow the selection of patients with high likelihood of responding to this therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3347. doi:1538-7445.AM2012-3347
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2012-3347
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2012
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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