Brain cancers are the leading cause of cancer-related deaths in children. A significant percentage of these tumors are classified as gliomas—diseases for which new therapies are desperately needed. A protein called tyrosine kinase FGFR1 is altered in 10% of pediatric gliomas. Dr. Apfelbaum aims to investigate critical genes in FGFR1-altered pediatric gliomas to understand the biological mechanisms driving these cancers. Her research hopes to uncover new therapeutic targets and mechanisms of FGFR1-mediated oncogenesis in pediatric gliomas, but since FGFR1 is commonly altered in many tumors, her findings may reveal a common oncogenic mechanism. Dr. Apfelbaum received her PhD from University of Michigan, Ann Arbor and her BS from Beloit College, Beloit.

Throughout brain development, neurons fire action potentials which are important to shape and refine brain connectivity, and this refinement occurs in part through dynamic changes in gene expression. Neuronal activity can also drive the progression of pediatric gliomas, underscoring a need to understand the molecular basis of activity-dependent gene expression in the brain. Dr. Duffy [National Mah Jongg League Breakthrough Scientist] is exploring how neuronal activity can drive local changes in gene expression by modulating RNA turnover and translation into proteins, and how these processes are misregulated in pediatric gliomas. She has identified cancer-associated mutations that disrupt RNA turnover in the brain and is interested in understanding the proteins that regulate this process as a mechanism to drive cancer progression. She has also developed high-throughput screening methods to test hundreds of disease-associated mutations in parallel to assay how they affect neuronal RNA turnover, which may reveal new molecular targets for cancer therapeutics.

Dr. Fang [HHMI Fellow] develops multiplexed imaging techniques to illuminate how enhancers control gene expression at a single cell level. Enhancer alterations are widely spread in cancer, but there is limited understanding of how these enhancers vary between single cells and relate to oncogene expression. Dr. Fang will generate single-cell regulatory networks to investigate how enhancer activities are disrupted in IDH-mutant cancers. The proposed work may help identify enhancer-based therapeutic targets for cancer treatment in the future.

Dr. Goel [Dale F. and Betty Ann Frey Fellow] is investigating structural and functional aspects of dopamine transmission in the brain, a key neuromodulator for motor and cognitive processes. Dopamine receptors have also been implicated in a variety of cancers, and recent evidence suggests that brain cancer (glioma) cells can form synaptic connections with neurons that drive tumor progression. To better understand the molecular organization that supports dopamine signaling, Dr. Goel will use super-resolution microscopy, modern genetic approaches, and functional measurements to assess the spatial organization of major dopamine receptors and determine the interplay between dopamine release and reception. This research aims to better understand the basic mechanisms of dopamine signaling, which may ultimately enable the design of novel therapies. 

A feared complication of malignant solid tumors is the development of brain metastases (BM), for which current treatments are limited and morbidity is high. While precision medicine approaches for BM have recently demonstrated promise, many patients are not able to benefit from this treatment approach as molecular analysis of BM tissue is not usually feasible. To address this obstacle, Dr. Kim [William G. Kaelin, Jr., MD, Physician-Scientist] will apply genomic profiling and deep learning methods to a rich dataset comprised of BM tissues, patient-matched brain MRIs, and cell-free DNA samples to develop techniques that reveal therapeutic targets within a patient’s BM. He hopes to identify ways to non-invasively characterize oncogenic drivers for a BM or monitor tumor evolution. These findings will demonstrate the potential of using algorithmic tools in the clinic to augment clinical decision-making and unlock opportunities for widespread application of precision medicine for BM.

Pediatric diffuse midline gliomas (DMG) are incurable brain cancers with no long-term survivors. To date, radiation therapy remains the standard of care but improves survival by only a few months. Despite intense research efforts over the past four decades, there is still a lack of mechanistic understanding of the biology underlying DMG radioresistance. Dr. Lo Cascio is studying how DMG tumors exploit interactions with surrounding normal neurons to survive radiation-induced cell death. While there is ample evidence that communication between neurons and DMG cells is critical to fuel tumor growth, whether this neuron-glioma crosstalk contributes to treatment failure is unknown. Dr. Lo Cascio hopes by pushing the boundaries of our knowledge of the neuron-glioma intercellular dialogue, she can identify resistance mechanisms that can be targeted to sensitize these lethal tumors to radiation therapy. Dr. Lo Cascio received her PhD from Arizona State University, Tempe and her BS from University of Bath, Bath.

Dr. Orellana Vinueza is investigating whether changes that modify the shape, stability and function of transfer RNAs (tRNAs) play a role in the development of cancer. The tRNA molecules are involved in the process that translates messenger RNA into a protein. Dr. Orellana Vinueza focuses on a tRNA methyltransferase complex that malfunctions in glioblastoma and liposarcoma. He will assess how alterations in the activity of this enzyme affect global patterns of methylation in normal and human cancer cells. Methylation is the process that controls the timing and amount of proteins that are produced in cells. Understanding how this process breaks down may help decipher the mechanisms that drive cancer and guide the development of new treatments.

Brain cancers are one of the most common causes of cancer-related death and represent 120 molecularly distinct diseases. Despite advances in clarifying the genetic landscape of these cancers, they remain clinically intractable, underscoring the need to elucidate the complex factors contributing to their heterogeneity. As neuronal activity is known to govern the development of neural circuits and neuroplasticity, it is critical to consider these neural networks in the context of disease. Dr. Venkatesh will use classical and systems neuroscience approaches to determine how the nervous system contributes to brain cancer progression. A comprehensive understanding of malignant neural network interactions may lead to novel therapeutic interventions aimed at normalizing the tumor microenvironment.

Dr. Wang [National Mah Jongg League Fellow] is investigating how brain cell activity (e.g., neurons “firing”) and the intracellular signaling pathways triggered by this activity influence glioma and pediatric brain cancer development. Using high-throughput approaches to map neuronal activity, gene expression, and cell structure at the single-cell level, Dr. Wang aims to understand the normal progression of these activity-dependent signaling pathways in the healthy brain, and how these mechanisms are hijacked during cancer progression. This work may reveal new molecular and cellular targets and lead to the development of novel therapeutic strategies. Dr. Wang received her PhD and MS from the University of Toronto, Toronto and her BS from the University of Western Ontario, London, Ontario.