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FALL 2022
Research Advancements: Brain Tumors
Mount Sinai Expands Brain Tumor Research Through Opening of the Children’s Brain and Spinal Tumor Center
P
ediatric brain and spinal tumors are the leading cause of diseaserelated death in children. There are ~4500 children diagnosed with a brain tumor annually in the United States with slightly more than half of the cases deemed aggressive or malignant. Although advances in clinical care have resulted in nearly 70-80% 5-year survival rates, the majority of survivors who receive therapies including systemic chemotherapy and/or radiation therapy are often left with significant morbidities. These include lower I.Q. scores, endocrine and growth deficiencies, and a risk of secondary malignancies. Furthermore, there are some pediatric brain tumor subtypes such as diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG), which have <10% survival at 2 years and <1-2% survival at 5 years. In response to improving the outcomes for these children, Mount Sinai recently created the Children’s Brain and Spinal Tumor Center following key faculty recruitments in several departments including Pediatrics and Neurology. Two of these physician-scientist recruits include Oren Becher, MD, a pediatric neuro-oncologist with expertise in DMG/DIPG who is Chief of the Jack Martin Fund Division of Pediatric Hematology-Oncology and Praveen Raju, MD, PhD, a pediatric neurologist with expertise in medulloblastoma, the most common malignant pediatric brain tumor. Notably, Dr. Becher and Dr. Raju have pioneered novel genetically-engineered mouse models of DIPG and medulloblastoma, respectively, that have served as the basis for recent studies that provide new insight into the biology of these brain tumors and open up therapeutic avenues. Dr. Becher has recently published an important paper exploring the pathogenesis of DMG. In a paper published in GLIA in May 2022, Dr. Becher describes a novel model of DMG initiated in oligodendrocyte progenitor cells, a cell type implicated as the cell of origin for DMG. Surprisingly, they found that the abnormal histone protein, H3K27M, did not promote cell growth in this model. These findings contrast with their prior DMG model initiated in stem cells in the brain. The only consistent effect of the abnormal histone protein across both models was inhibition of immune system activation by the abnormal histone protein. These findings suggest that it will Praveen Raju, MD, PhD Associate Professor, Neurology & Pediatrics Director, Pediatric Onco-Neurology & Neurofibromatosis Clinic Director, Pediatric Neurology Residency Program Associate Director, Medical Scientist Training Program (MSTP)
be challenging to successfully treat DMGs with therapies that aim to activate the immune system against the cancer cells without also blocking the abnormal histone protein. Dr. Raju has developed a novel mouse model of medulloblastoma using sophisticated mosaic mutagenesis approaches that recapitulates the distinct tumor histologies and frequent leptomeningeal metastases seen in patients but rarely found in animal models. Importantly, this medulloblastoma model maintains a tight blood-brain barrier (BBB) that has hindered efforts to deliver high drug concentrations into the brain and partly explains the poor outcomes for these children. In collaboration with chemical biology colleagues, Dr. Raju has recently advanced a novel fucoidan-based nanomedicine platform that allows reformulation of several classes of anti-cancer drugs that can penetrate through a tight BBB specifically at the site of the brain tumor via an active transport mechanism that requires caveolin-1-mediated transcytosis. This work is available as a preprint and has recently been accepted for publication in Nature Materials.
Key References 1. Tomita Y, Shimazu Y, Somasundaram A, Tanaka Y, Takata N, Ishi Y, Gadd S, Hashizume R, Angione A, Pinero G, Hambardzumyan D, Brat DJ, Hoeman CM, Becher OJ*. A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M. Glia 2022; 70(9):1681-1698. 2. Tylawsky D, Kiguchi H, Vaynshteyn J, Gerwin J, Shah J, Islam T, Snuderl M, Greenblatt M, Boue D, Shamay Y, Raju GP*, Heller DA*. P-selectin targeting stimulates caveolin-1-mediated endothelial transcytosis in medulloblastoma. preprint DOI:10.21203/ rs.3.rs-658944/v1 3. Mount Sinai Children’s Brain and Spinal Tumor Center: https://icahn.mssm.edu/research/cbstc
Oren Becher, MD Professor, Pediatrics & Oncological Sciences Steven Ravitch Chair in Pediatric Hematology-Oncology Chief, Jack Martin Fund Division of Pediatric HematologyOncology