Abstract 5587: An objective clustering of GBM patients to identify clinically relevant subgroup with Hedgehog pathway activity.

Abstract

A targeted therapy with lesser or no toxicity is an immediate need for glioblastoma multiforme (GBM). A group of Hedgehog (Hh) pathway inhibitor drugs is one among the most promising targeted therapies in a wide number of malignancies including medulloblastoma, a lethal childhood central nervous system (CNS) malignancy, about a third of which is presented with high Hh pathway activity. However, in case of GBM a great degree of ambiguity is reported in terms of this pathway activity. GBM is known to be highly heterogeneous at molecular level. It is indeed not clear whether any specific subgroup of GBM shows considerable Hh pathway activity so that could be targeted with appropriate Hh pathway inhibitory drugs. We estimated here the mRNA expression levels of 7 Hh pathway component genes — the ligand Sonic Hedgehog (SHH), trans-membrane receptors Patched (PTCH1) and Smoothened (SMO), Hh transcription factors Gli-1 (GLI1), Gli-2 (GLI2) and Gli-3 (GLI3), and also the Gli-1 target gene Snail (SNAI1), relative to the levels of β-actin expression, by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) method, in a cohort of GBM patients from the Eastern part of India. We have so far estimated the relative expression levels of these genes in 10 GBM, 8 low grade astrocytoma, 2 meningioma, 2 schwannoma, 1 medulloblastoma biopsy samples and 2 normal cerebellar tissue samples. CNS tumors with astrocytic origin were confirmed by Glial fibrillary acidic protein (GFAP) mRNA expression. We selected only the GBM cases for further analysis in the present study. We calculated the squared Pearson correlation coefficient between expression levels (2–ΔCt) of all the 7 genes and found the best correlations between three of them — SHH, GLI1 and SNAI1 respectively. High correlation of the expression of SHH with that of GLI1 (r2 = 0.9964) is suggestive of ligand-driven mechanism of this pathway activity in this disease. Although both PTCH1 and SNAI1 are bona fide targets of the Hh transcription factor GLI1, interestingly, we observed that the expression of GLI1 had a low correlation with that of PTCH1 (r2 = 0.0472) but was highly correlated with SNAI1 expression (r2 = 0.9986). Moreover, by using k-means clustering analysis three subgroups of patients were identified based on their expression patterns of all 7 Hh pathway component genes that were included in the present study. We have found detectable levels of SMO mRNA in all GBM patients included in the study so far, suggesting a potential benefit of the targeted therapy with smoothened antagonist drugs in this disease. Citation Format: Tapojyoti Das, Uttara Chatterjee, Samarendra Nath Ghosh, Sumit Deb, Suniti Kumar Saha, Puneet Gulati, Sarang Rote, Vikas Chandra, Ankur Mukherjee, Surajit Dhara. An objective clustering of GBM patients to identify clinically relevant subgroup with Hedgehog pathway activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5587. doi:10.1158/1538-7445.AM2013-5587

SH2B3, Transcribed by STAT1, Promotes Glioblastoma Progression Through Transducing IL-6/gp130 Signaling to Activate STAT3 Signaling

“…To further determine the underlying molecular mechanism by which SH2B3 regulates GSCs' self-renewal, we assessed four major self-renewal signaling pathways, including Hedgehog (Das et al, 2013), Wnt/β-catenin (Nitta et al, 2013), Notch (Man et al, 2018), and STAT3 (Shi et al, 2017) signaling pathways, in which both of them are key regulators that have been well established to regulate GSCs' self-renewal. We found that only STAT3 target genes, including STAT3 and SOCS3, were remarkably decreased in U87 and U251 SH2B3-deficient cells (Figure 6A).…”