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Abstract Details

Promoter Methylation-Dependent Silencing of Cell Cycle Tumor Suppressors in Aggressive PNET Is Overcome by Perifosine and HDAC Inhibitors
Neuro-oncology
IN10 - (-)
004
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.
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.
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.
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
Benjamin M. Greenberg, MD, FAAN (UT Southwestern Medical Center) Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Greenberg has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Greenberg has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amgen. Dr. Greenberg has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi/Genzyme. Dr. Greenberg has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech/Roche. Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant. Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for IQVIA. Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Greenberg has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Clene. Dr. Greenberg has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG Therapeutics. Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for IQVIA. Dr. Greenberg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abcuro. Dr. Greenberg has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Siegel Rare Neuroimmune Association. Dr. Greenberg has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Husch Blackwell. Dr. Greenberg has stock in GenrAb. Dr. Greenberg has stock in Clene. The institution of Dr. Greenberg has received research support from Anokion. The institution of Dr. Greenberg has received research support from Regeneron. Dr. Greenberg has received intellectual property interests from a discovery or technology relating to health care. Dr. Greenberg has received publishing royalties from a publication relating to health care.