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 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
Priscilla K. Brastianos, MD

Brain metastases are the most common tumor in the brain, most frequently originating from melanoma and carcinomas of the lung and breast. Of patients who develop brain metastases, approximately half succumb to the cancer in their brain. Unfortunately, treatment options are limited, and most current clinical trials in the US exclude patients with brain metastases. Dr. Brastianos recently completed a large study to understand the genetic changes that occur in brain metastases. She identified genetic alterations in brain metastases that predict sensitivity to targeted therapies. She will conduct a biomarker-driven Phase 2 study to evaluate targeted therapy in patients with brain metastases harboring specific genetic alterations. Her research will incorporate cutting-edge genomic technology and animal models to understand predictors of response, as well as resistance to targeted therapies. As most genomically guided trials in cancer have excluded patients with active brain metastases, this represents a potential paradigm shift in the management of patients with brain metastases.

Project title: "Investigation of novel targeted therapeutic approaches for brain metastases"
Institution: Massachusetts General Hospital
Award Program: Clinical Investigator
Sponsor(s) / Mentor(s): Keith T. Flaherty, MD and Tracy T. Batchelor, MD
Cancer Type: Brain
Research Area: Invasion and Metastasis
Amelia N. Chang, PhD

Dr. Chang is investigating the role of activity-regulated gene expression in human brain evolution. Activity-regulated pathways control critical brain functions and modulate tumor growth in multiple cancers. These pathways are broadly conserved across all mammals, but newer studies have identified features that are unique to primates and may influence important aspects of brain function and tumor progression. Dr. Chang will study the function, regulation, and evolution of primate-specific genes. Through these experiments, she aims to uncover molecular insight into what makes humans susceptible to cancer.

Project title: "The role of activity-regulated gene expression in human brain evolution"
Institution: Harvard Medical School
Award Program: Fellow
Sponsor(s) / Mentor(s): Michael E. Greenberg, PhD
Cancer Type: Brain
Research Area: Neuroscience
Erin E. Duffy, PhD

Dr. Duffy is investigating how neuronal activity can regulate gene expression through a potentially novel mechanism in the developing brain, called RNA turnover. This mechanism may enable gene expression to be rapidly and locally controlled at individual connections between neurons based on neuronal activity. There is evidence that neuronal activity may contribute to pediatric malignant glioma brain tumors. Dr. Duffy aims to characterize this process and identify new therapeutic targets for pediatric brain cancer.

Project title: "Activity-dependent changes in RNA stability as a mechanism for synaptic plasticity"
Institution: Harvard Medical School
Award Program: Fellow
Sponsor(s) / Mentor(s): Michael E. Greenberg, PhD
Cancer Type: Brain
Research Area: Neuroscience
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.

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
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
Marcela V. Maus, MD, PhD

Dr. Maus is engineering the body's own immune T cells to fight deadly brain tumors like glioblastoma. However, in studies of patients with brain tumors, she has found that tumor cells can escape the engineered T cells. She is now redesigning T cells so that they block escape routes used by the tumors. She expects that the engineered cells will be more powerful and may become a new effective treatment for brain tumors. The engineered CAR T cells are designed to target cells displaying multiple abnormal proteins (antigens) made from cancer-causing oncogenes; they will act as drug carriers to address the specific hurdles of antigen heterogeneity and penetrating the blood brain barrier. She is testing these "living drugs" in vitro and in mouse models with the goal of ultimately advancing these studies to human clinical trials. Furthermore, if this system works for brain tumors, it has the potential to be applied as a therapy for other forms of cancer as well.

Project title: "Next-generation CAR T cells for EGFRvIII-positive glioblastoma"
Institution: Massachusetts General Hospital
Award Program: Innovator
Cancer Type: Brain
Research Area: Immunotherapy
Nagarajan Nandagopal, PhD

Dr. Nandagopal 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 Megason, PhD
Cancer Type: Other Cancer, Brain
Research Area: Systems Biology
Natasha M. O'Brown, PhD

Dr. O'Brown is investigating the molecular mechanisms that govern the blood-brain barrier (BBB), which acts as the gatekeeper for the brain. While the BBB protects the brain from pathogens and provides the necessary environment for normal brain function, the BBB also acts as an obstacle to drug delivery for the treatment of neurological diseases, including brain tumors. A key regulator of BBB integrity, Mfsd2a, limits transcellular movement across the barrier and therefore prevents leakage into the brain. Using a combination of zebrafish genetics, small molecule screens, and live imaging, she aims to understand how this protein regulates these BBB processes. By investigating the cellular signals that induce or remove barrier properties, she hopes to identify ways by which she can selectively manipulate the barrier to allow for drug delivery to the brain.

Project title: "Molecular and cellular mechanisms of transcytosis regulation in blood-brain barrier function"
Institution: Harvard Medical School
Award Program: Dale Frey Scientist, Fellow
Sponsor(s) / Mentor(s): Sean G. Megason, PhD, and Chenghua Gu, PhD
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.)
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