Without new treatment options, patients diagnosed with glioblastoma brain tumors continue to have poor survival outcomes. Dr. Aquilanti [The Ben and Catherine Ivy Foundation Physician-Scientist] aims to validate a new drug target called telomerase, a protein complex that elongates telomeres that cap the ends of chromosomes. Telomeres shorten with each cell division until they reach a critical length, and the cell stops dividing or dies. Many tumors activate telomerase to prevent the telomeres from shortening so their cells can divide indefinitely. Telomerase activation may be one of the main drivers of glioblastoma, occurring in over 85% of cases. Once she demonstrates that telomerase activity leads to cell death in glioblastoma, she hopes to develop a novel tool for screening drugs that can target telomerase. Additionally, she will explore whether alternative telomere maintenance pathways can develop in response to telomerase inhibition.

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 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.

The blood-brain barrier acts as the gate-keeper to the brain and is critical for proper neuronal function. While the barrier normally acts to protect the brain from toxins and pathogens, it is also a huge obstacle for drug delivery to effectively treat brain tumors. Dr. O’Brown studies the molecules that regulate blood-brain barrier development and function. By understanding how the barrier is normally formed and which molecules are necessary to keep the barrier intact, she can then genetically or chemically tweak these molecules to open the barrier and allow for better treatment of brain cancers.

Dr. Touhara [Robert A. Swanson Family Fellow] is focusing on enteroendocrine cells which are found in the wall of the gut and secrete hormones that regulate glucose levels, food intake and stomach emptying. Abnormal activity of these cells often causes common gastrointestinal disorders such as irritable bowel syndrome and carcinoid tumors. Dr. Touhara aims to elucidate interactions of the enteroendocrine cells with the enteric nervous system which controls gut motility and communicates with the brain. This research may lead to new drug targets and treatments for disorders of the gut.

Glioblastomas are the most common and aggressive primary brain tumors in adults. Despite intensive treatment with therapies such as radiation, these tumors inevitably recur, and fewer than 10% of glioblastoma patients live longer than 5 years after diagnosis. Dr. Wahl and his research team have found that metabolites called purines, which are the building blocks that make up DNA, make glioblastomas resistant to treatments like radiation. Dr. Wahl will use patient samples and mouse models to determine what regulates glioblastoma purine metabolism and whether inhibition of these metabolic pathways can make radiation more effective. He will also perform a clinical study to directly measure these metabolic pathways in patients with glioblastoma.

Dr. Wang 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.