Brain and Central Nervous System Tumors

Current Projects
Elisa A. Aquilanti, MD

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.

Project title: "Targeting telomerase in glioblastoma"
Institution: Dana-Farber Cancer Institute
Named Award: The Ben and Catherine Ivy Foundation Physician-Scientist
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Matthew L. Meyerson, MD, PhD
Cancer Type: Brain
Research Area: Drug Discovery
Rongxin Fang, PhD

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.

 
Project title: "Genome-scale imaging of enhancer-promoter interactions in cancer at single cell resolution"
Institution: Harvard University
Named Award: HHMI Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Xiaowei Zhuang, PhD
Cancer Type: Brain
Research Area: Imaging
Siting Gan, PhD

Dr. Gan focuses on brain metastasis in lung and breast cancer, a major cause of death for these patients. She is applying the latest single-cell technologies and developing computational tools to dissect how tumor cells interact with resident brain cells to mediate the progression of metastasis. This research aims to better understand the formation of brain metastasis which may lead to new therapeutic strategies for prevention.

Dr. Gan is developing computational methods to leverage the approximate spatial information of whether a brain cell is near a metastatic tumor cell and coarse tumor progression indicators, such as the postinoculation time and whole-brain ex vivo bioluminescence signal to infer the trajectories of phenotypic states in each type of cell. She is applying these methods to examine how the different populations of cells influence each other to co-evolve along their respective trajectories.

Project title: "In situ single-cell dissection of the tumor-microenvironment interplay mediating brain metastasis"
Institution: Memorial Sloan Kettering Cancer Center
Award Program: Quantitative Biology Fellow
Sponsor(s) / Mentor(s): Joan Massagué, PhD, and Dana Pe'er, PhD
Cancer Type: Brain, Breast, Lung
Research Area: Systems Biology
Pragya Goel, PhD

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. 

Project title: "Signaling structure for neuromodulatory coding in the vertebrate striatum"
Institution: Harvard Medical School
Named Award: Dale F. and Betty Ann Frey Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Pascal Kaeser, MD
Cancer Type: Brain
Research Area: Neuroscience
Christina L. Hueschen, PhD

Dr. Hueschen studies the motility of Apicomplexan parasites, which cause malaria, foodborne illness (toxoplasmosis) and infections in immunocompromised cancer patients. These parasites move through the human body using a mechanism called "gliding" to migrate over host cells and through the surrounding extracellular matrix. Dr. Hueschen's goal is to understand how molecules inside the parasite are organized, coordinated and regulated to produce forces that direct movement. This research has the potential to aid in the development of therapies to prevent opportunistic infections.

Project title: "Molecular basis and regulation of apicomplexan parasite motility"
Institution: Stanford University
Award Program: Fellow
Sponsor(s) / Mentor(s): Alex Dunn, PhD
Cancer Type: Gastric, Brain, Colorectal, All Cancers
Research Area: Cell Biology
Albert E. Kim, MD

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.

Project title: "Using liquid biopsy and MRI to non-invasively identify therapeutic targets for brain metastases"
Institution: Massachusetts General Hospital
Named Award: William G. Kaelin Jr. MD Physician-Scientist
Award Program: Physician-Scientist
Sponsor(s) / Mentor(s): Priscilla K. Brastianos, MD, and Elizabeth R. Gerstner, MD
Cancer Type: Brain
Research Area: Cancer Genetics
Nagarajan Nandagopal, PhD

Dr. Nandagopal [Philip O’Bryan Montgomery Jr. MD Fellow] is focusing on genes in the bHLH family and their role in signal integration to help decide whether cells grow and divide, differentiate, migrate, or even die. bHLH genes are involved in fate choices in stem cells of the brain, intestines, skin, and other tissues. They are also commonly misregulated in cancers, such as neuroblastomas and glioblastomas. By comparing signal integration by bHLH circuits in normal and cancer cells, Dr. Nandagopal aims to discover how errors in fate decisions occur, and how they can be corrected. 

Project title: "Signal integration by bHLH circuits to enable cell fate decisions"
Institution: Harvard Medical School
Named Award: Philip O’Bryan Montgomery Jr. MD Fellow
Award Program: Fellow
Sponsor(s) / Mentor(s): Galit Lahav, PhD, and Sean G. Megason, PhD
Cancer Type: Other Cancer, Brain
Research Area: Systems Biology
Natasha M. O'Brown, PhD

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.

Project title: "Molecular and cellular regulators of blood-brain barrier function"
Institution: Harvard Medical School
Award Program: Dale Frey Scientist
Cancer Type: Brain
Research Area: Developmental Biology
Esteban A. Orellana Vinueza, PhD

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.

Project title: "Role of METTL1-WDR4 tRNA methyltransferase complex in cancer"
Institution: Boston Children's Hospital
Award Program: Fellow
Sponsor(s) / Mentor(s): Richard I. Gregory, PhD
Cancer Type: Brain, Sarcoma
Research Area: RNA (RNA processing, miRNA and piRNA mechanisms, enzymatic RNAs, etc.)
Zulekha A. Qadeer, PhD

Dr. Qadeer investigates the mechanisms underlying medulloblastoma (MB), the most common form of malignant brain tumors in children. Group 3 MB is a particularly aggressive subgroup, for which there are few actionable targets for therapies. Dr. Qadeer aims to understand how the genes and pathways regulated by the proteins MYC and TGFb mediate the transformation of neural precursor cells to malignant group 3 MB tumors. This work may also help elucidate tumor heterogeneity and resistance to current alkylating chemotherapies. The overall goal of this research is to identify more effective therapies to treat patients by targeting the mutations that drive tumor formation.

Project title: "Targeting TGFb pathway dependencies in Group 3 Medulloblastoma" 
Institution: University of California, San Francisco
Award Program: Sohn Fellow
Sponsor(s) / Mentor(s): William A. Weiss, MD, PhD
Cancer Type: Pediatric, Brain
Research Area: Invasion and Metastasis
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