DIPGs are rapidly lethal brain tumors of childhood. The majority of patients die within a year or two of diagnosis, as there is no effective treatment for this devastating disease. Their critical location in the brainstem has long prohibited access to tumor tissue. Recently, sequencing studies revealed novel histone mutations consisting of single amino acid substitutions in the tail of the histone H3 variants. A pattern of exclusive co-occurrence of histone mutations with specific signaling pathway alterations as well as age of onset and brain region alterations emerged. Taking advantage of these data and of the strict developmental window of the tumors, our team has built what is effectively the first genetically-engineered human ES cell-based model of a tumor. The model yielded tumors that recapitulated the genetic, transcriptomal, epigenetic and histological features of the disease, thus providing valuable tools for the study of the disease. Genome wide studies suggested that the histone mutation led to a resetting of the developmental status of the cells to an earlier more primitive stem cell state. Importantly, our modeling system served as an effective platform for drug screens, leading to the identification of a novel protein ?protein interaction network as a key component of the proliferative and growth machinery of these tumors, centered on the protein menin. Menin is a unique protein with multiple partners; it is oncogenic in the context of the MLL rearranged leukemias. Our data show that silencing menin or inhibiting its MLL interaction with a menin inhibitor leads to a decrease in proliferation and increased cell death, a completely novel finding never reported in glioma, that raises the promise of a therapeutic strategy. The proposal aims to expand our hES modeling platform by building new models that are representative of the genetic diversity of the somatic mutations described in brainstem gliomas. We will also study the events downstream of the histone mutations, with emphasis on the molecular basis of the oncogenic role of menin. The ultimate goal is to develop a therapeutic strategy for DIPGs, taking advantage of newly synthesized menin inhibitors. Our studies should also contribute to developing hES cells into a more widely applicable platform for cancer modeling capitalizing on their many advantages, including access to an unlimited supply of stage appropriate human cells for mechanistic or therapeutic studies, the ability to study tumor biology from the step of initiation to tumor maintenance, and the ease of implementing sophisticated genetic tools.

Public Health Relevance

Diffuse intrinsic pontine gliomas are devastating tumors of the brainstem of children, that have no effective treatment and very poor access to tissue. Our team has experience in differentiating stem cells into brain cells, and designed a successful model of the disease, as well as a promising drug target. In this proposal we will expand the model to cover a wider range of brainstem tumors, further investigate the tumors' biology and develop a treatment strategy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Mietz, Judy
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Sloan-Kettering Institute for Cancer Research
New York
United States
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