Abstract Details

Title Promoter Methylation-Dependent Silencing of Cell Cycle Tumor Suppressors in Aggressive PNET Is Overcome by Perifosine and HDAC Inhibitors

Topic Neuro-oncology

Presentation(s) S35 - (-)

Poster/Presentation
Number 003

Objective

Background Methylation-dependent gene silencing has been reported to be one mechanism by which medulloblastomas evade growth control mechanisms. Supratentorial PNET have a very aggressive clinical course, and have not been well characterized.

Design/Methods Primary tumor tissue, short term PNET cultures and their xenografts were examined for P21 and P16 expression by quantitative RT-PCR prior to and following treatment for 24 hours with perifosine, CUDC101, SAHA and valproic acid, compared to non-tumor CNS stem cell cultures and normal brain samples. Extracts were subjected to bisulfite sequencing and the results compared. Changes in expression levels of P21,P16 and cell lineage and differentiation markers were assayed by Taqman qRT-PCR assay, confocal imaging and western blotting.

Results Bisulfite sequencing revealed that both genes were methylated at cytosine residues within and outside of typical CpG islands. A similar reversal of cytosine methylation was observed after treatment with histone deacetylase (HDAC) inhibitors SAHA, CUDC101 and valproic acid. The reactivation of p16 and p21 in multiple tumor models was sufficient to overcome noted amplifications in the Cyclin/CDK pathway and produced significant attenuation of tumor growth, leading an increase in expression of terminal differentiation markers.

Conclusions These data indicate that treatment of sPNET with the multikinase inhibitor perifosine, or with HDAC inhibitors already in clinical trials may be dependent upon reversal of DNA methylation-mediated silencing of p21 and/or p16, and provide a way of assaying the therapeutic response of treated tumors within future clinical trial designs.

Authors/Disclosures
Anil Kumar, MD (Great Plains Health) PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Giancarlo Comi, MD (University Vita-Salute)	Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Janssen. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Aspen Healthcare. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sanofi. Dr. Comi has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Rewind.

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