Targeting a Novel Epigenetic Signature in Diffuse Intrinsic Pontine Gliomas

Lay Summary: Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most lethal of all pediatric brain cancers. Surgical removal is nearly impossible; they are resistant to all known chemotherapies and the positive effects of radiation therapy are temporary at best. Sadly, the majority of children die within two years of diagnosis. Therefore, novel therapeutic approaches are urgently needed. Genetic profiling has revealed that over 85% of DIPGs acquire a specific dominant-negative mutation in one of the 15 copies of histone H3 genes that encode the proteins that package their DNA genomes into chromatin. This specific mutation greatly impacts the chemical modifications that occur on the histone proteins. Such histone modifications are often referred to as “epigenetic” as they affect the expression of the genes that they package. We identified one such epigenetic modification (H3K36me2) that is massively elevated in DIPG tumor cells. In addition, we discovered the proteins that specifically bind this modification and uncovered their basic biological function: they maintain the expression of genes found in the chromatin to which they are bound.

Project Goal: With chemists at The University of Toronto, we have developed preliminary compounds that block the ability of these proteins to bind to this epigenetic modification. We are also working to develop compounds that inhibit the enzymes that cause the elevation of this modification. Further in vivo testing of these compounds in transgenic mice engineered with DIPG tumors will be carried out here at NYU. These compounds are promising therapeutics for the treatment of this deadly childhood malignancy.

Project Update 2022: Our latest work has demonstrated that the inhibition of either the proteins (NSD1 and NSD2) that synthesize the H3K36me2 modification or the proteins (LEDGF and HDGF2) that bind the H3K36me2 modification is detrimental to the proliferation of these tumors. This work highlights the feasibility of developing drugs that inhibit these proteins for treatment of this deadly disease. With chemists we are developing compounds that inhibit proteins that synthesize the H3K36me2 modification (NSD1 and NSD2) and compounds that block the proteins (LEDGF and HDGF2) that bind the H3K36me2 modification. In vivo testing of these compounds in transgenic mice engineered with DIPG tumors will be carried out here at NYU. These compounds are very promising therapeutics for the treatment of this deadly childhood malignancy.