2014 ABTA-funded Research Outcomes Summaries

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BASIC RESEARCH FELLOWSHIPS (2012-2014)
The American Brain Tumor Association Basic Research Fellowship is a two-year fellowship designed to encourage talented scientists early in their careers to enter, or remain in, the field of brain tumor research.

 

PRISCILLA KALIOPI BRASTIANOS, MD
Dana-Farber Cancer Institute/ Harvard Medical School, Boston, MA
Project Title: “Genomic Characterization of Brain Metastases”
American Brain Tumor Association Basic Research Fellowship Supported by the Bradley Benton Davis Memorial Foundation

Summary: Brain metastases are the most common brain tumor in adults. The genetic and molecular mechanisms that drive metastasis to the brain remain poorly understood. Through collaborations with multiple institutions throughout the world, we collected a large sample set of matched brain metastases and primary tumors and we used the latest sequencing techniques to study how brain metastases evolve from their primary tumors. We found that brain metastases acquire new mutations that are not present in the primary tumor. This has implications for how we treat brain metastases. Additionally we studied the genomics of other tumor types, including meningiomas and craniopharyngiomas. We discovered novel recurrent mutations in meningiomas, for which there are targeted therapies in use in other cancers. The next steps include targeting these mutations in a multicenter Phase II clinical trial.

 

YI-HSIEN CHEN, PHD
Washington University School of Medicine, St. Louis, MO
Project Title: “Identification of Cellular and Molecular Targets for KIAA1549: BRAF-Induced Pediatric Glioma Therapy”
American Brain Tumor Association Basic Research Fellowship Supported by The Emily Dorfman Foundation for Children in Memory of Emily Ann Dorfman
Summary: The majority of pilocytic astrocytoma (PA) brain tumors occur sporadically in children and harbor a genetic mutation on BRAF gene. In tumor cells, an unknown gene fused to the BRAF kinase region results in the abnormal form of BRAF, known as f-BRAF. This research was able to show that f-BRAF expression results in increased cell growth, sufficient for gliomagenesis, when it is placed in neural stem cells from the cerebellum, but not in neural stem cells from the cortex or mature glia cells from the cerebellum. We identified that f-BRAF regulates cellular growth pathway, mammalian target of rapamycin (mTOR), that is also observed in NF1-associated PAs. Overall, these results suggest that mTOR acts as a key growth regulatory pathway in sporadic and familial low-grade gliomas in children, and could be a potential target for therapeutic intervention.

 

ARTHUR P. CHOU, MD, PHD
University of California Los Angeles, Los Angeles, CA
Project Title: “Abnormal DNA Methylation and Retinoic Acid Signaling in Gliomas with Isocitrate Dehydrogenase 1 (IDH1) Mutation”
American Brain Tumor Association Basic Research Fellowship Supported by Mr. & Mrs. William L. Jackson in Honor of Bruce Jackson
Summary: Our long term goal is to understand the molecules and mechanisms that control glioma formation.  To do so, we have been studying gliomas arising along a pathway characterized by the presence of a novel mutation in the isocitrate dehydrogenase gene (IDH1). This mutation is found in over one third of all diffuse gliomas. Specifically, we are studying DNA changes found to be associated with gliomas harboring this mutation. These DNA changes are called ‘epigenetic’ modifications in which methylation marks are placed at important regions of the DNA and altering its function. We used state of the art technology to map the location of methylation marks associated with glioma and used these maps to identify altered genes that may be involved in glioma formation; and further studied the functions of these altered genes, with the goal that we can design specific therapies to target these gene alterations.  

 

JANE ENGLER, PHD
University of California San Francisco, San Francisco, CA
Project Title: “The Role of the Tumor Associated Microglial/Macrophage Response in Glioma Cell Invasion”
American Brain Tumor Association Basic Research Fellowship in Honor of Joel A. Gingras, Jr.
Summary: The tumor-associated immune response is known to play an important role in disease for many cancers. We have demonstrated that molecular subtypes of glioblastoma differ with respect to both the number of microglia/macrophages and the expression of microglia/macrophage signature genes. In addition, we have shown that the expression of immune response genes is enriched in patients with the short survival. These data strongly suggest that the tumor-associated immune response differs across tumors with different molecular alterations. Current studies in the laboratory use a murine model for GBM to determine how tumor intrinsic factors drive differences in the tumor-associated microglia/macrophage response. The potential implications of these data are broad as differences in the immune response may influence the response to immunomodulatory therapies.

 

LORI (MAINWARING) RAMKISSOON, PHD
Dana-Farber Cancer Institute, Boston MA
Project Title: “The Role of Sox2 in Normal Neural Stem Cell Development and Gliomagenesis”
American Brain Tumor Association Basic Research Fellowship in Honor of Joel A. Gingras, Jr.
Summary: The transcription factor SOX2 is a master regulator in stem cells with the ability to induce differentiated cells into a state of plasticity. In addition to regulating the decision of a normal neural stem cell to become an astrocyte or a neuron, SOX2 is hypothesized to play critical roles in brain cancer.  Indeed SOX2 is the highest expressed transcription factor in GBM and is found in greater than 90% of tumor cells. To understand the signaling networks regulated by SOX2, a ChIP-Sequencing on GBM cell lines was performed. These data suggest that although SOX2 regulates a network critical for ESCs, NSCs and GBM cells, the majority of its functions are unique to each cell lineage. When SOX2 levels were specifically increased in the brain, defects in the organization and migration of granule neurons in the cerebellum were observed. 

BRADEN C. MCFARLAND, PHD
University of Alabama at Birmingham, Birmingham, AL
Project Title: “Determining the Molecular Mechanisms of Crosstalk Between the NF-κB and JAK/STAT-3 Signaling Pathways in Glioblastoma”
American Brain Tumor Association Basic Research Fellowship in Honor of Paul Fabbri
Summary: Over the years, there have been many cellular signaling pathways that have been linked to GBM growth. The focus of this project was to reveal the mechanisms of crosstalk between these two pathways to more accurately develop pharmacological interventions. We have discovered that STAT-3 and NF-κB participate in a cycle of crosstalk, and we have shown that combination treatment with pharmacological inhibitors is more effective than single drug treatment. In addition, this project was expanded to include a new model of brain tumors, evaluating the interaction between the tumor and the immune system. Currently, plans are underway for a Phase I clinical trial for patients with GBM based on the results of this project.

 

CHAD MYSKIW, PHD
Salk Institute for Biological Studies, La Jolla, CA
Project Title: “The Role of Long Non-Coding RNAs in Glioblastoma Progression and Angiogenesis”
American Brain Tumor Association Basic Research Fellowship Supported by the GBM Research Fund
Summary: Most studies in cancer biology have focused on studying genes that make proteins. However, it is now known that many genes in the human genome make RNA which does encode protein, so-called “non-coding RNA”. We have generated a comprehensive profile of the non-coding RNAs expressed in glioblastoma. We found that many of these non-coding RNA genes are produced at different levels in tumor tissue compared to normal tissue. This suggests that some of these non-coding RNA genes may play a role in helping the tumor grow. It is our hope that this work will identify novel targets for therapeutic intervention in glioblastoma. 

 

SUJAN PIYA, PHD
MD Anderson Cancer Center, Houston, TX
Project Title: “Understanding Regulation of Autophagy in Gliomas Infected with Delta-24-RGD Oncolytic Adenovirus”
American Brain Tumor Association Basic Research Fellowship Supported by Stephen M. Coffman Charitable Trust
Summary: Genetic alteration and immune privilege are the main factors in treatment options for malignant gliomas. A targeted Delta 24-RGD Oncolytic adenovirus was developed in our lab. The clinical trials of this virus show autophagy followed by lysis of tumor cell leading to elimination of tumor in most patients. We aimed to prompt prolong replication and spreading virus in the heterogeneous population of glioma cells by maintenance of autophagy. Our study showed that adenovirus early gene express E1B protein to regulate and maintenance of autophagy machinery resulting enhanced autophagy and exploit the host to generate enough population of virus in the tumor and eventually leading oncolysis of tumor in late phase. Collectively our study shed light in understanding the regulation of autophagy in virotherapy and open new avenue in treatment of brain tumor with Delta 24-RGD Oncolytic adenovirus.

 

AN-CHI TIEN, PHD
University of California San Francisco, Institute of Regenerative Medicine, San Francisco, CA
Project Title: “Pediatrics Glioma: Cellular Origins and Oncogenic Signaling”
American Brain Tumor Association Basic Research Fellowship Supported by The Emily Dorfman Foundation for Children in Memory of Emily Ann Dorfman
Summary: BrafV600E mutation has been identified in 10%-25% of grade II-IV pediatric glioma. In a genetically similar mouse model, prolonged and increased proliferation rate is observed in one of the glial cell types: oligodendrocyte precursor (OLPs). These proliferative OLPs express several known cancer stem cell markers including Olig2, Sox2, Mash-1 and SSEA-1, suggesting that they are the cell-of-origin causing pediatric glioma formation. We focused on phosphorylation of Olig2 and identified two kinases: GSK-3B and CK-II that phosphorylate Olig2 in BrafV600E-driven neurospheres. Inhibition of CK-II results in decreased in p-Olig2 levels and in OLP proliferation rate. Further pre-clinical studies are underway to validate the possible drugability of CK-II inhibitor. Our work suggests novel inhibitor therapy in a subset of Braf-driven pediatric glioma.

 

 

DISCOVERY GRANTS (2013-2014)
The American Brain Tumor Association Discovery Grant is a one year award supporting high risk/high impact projects that have the potential to change current diagnostic or treatment paradigms for either adult or pediatric brain tumors.

HENK M. DE FEYTER, PHD
Yale University, Magnetic Resonance Research Center (MRRC), New Haven, CT
Project Title: “13C Magnetic Resonance Spectroscopy (MRS) Methods for Quantitative in vivo Measurement of Brain Tumor Metabolism”
American Brain Tumor Association Discovery Grant
Summary: Our project aimed at modifying and implementing a carbon-13 magnetic resonance spectroscopy (13C MRS) technique to study metabolism of brain tumors in patients. This method uses the same scanner as for standard magnetic resonance imaging (MRI). We have successfully implemented a novel imaging application that allows to measure how brain tumors use sugar for their energy provision. Brain tumors are suspected to use sugar from the blood in different ways than normal brain tissue. Even between different brain tumor types one can expect variations in how the blood sugar is processed (for instance, how fast is the blood sugar consumed or which chemical process is the most important). Currently it is necessary to get a small piece of the tumor tissue through a biopsy to find out with certainty what type of tumor a patient has. If we can use MRI scanners to show these differences it can become easier to identify the type of tumor and a biopsy may not be needed.

 

STACY MCCARTY, MD
The Rehabilitation Institute of Chicago, Chicago, IL
Project Title: “Health-related Quality of Life and Cancer-related Symptoms during an Interdisciplinary Outpatient Rehabilitation for Malignant Brain Tumors”
American Brain Tumor Association Discovery Grant
Summary: The objective of this project was to determine if an interdisciplinary outpatient rehabilitation program will improve health-related quality of life (HRQOL), pain, and depression in patients with malignant brain tumors at the conclusion of rehabilitation and at 1 and 3 months follow up. Patient-reported HRQOL was stable throughout the rehabilitation program. Most HRQOL domains were associated with depression during the program and follow-up periods. Results suggest an interdisciplinary outpatient rehabilitation program for malignant brain tumor patients should also address symptoms of depression in order to improve overall HRQOL.

 

RAJESH MUKTHAVARAM, PHD
Moores Cancer Center, University of California San Diego, La Jolla, CA
Project Title: “Identification of Potential OLIG2 Inhibitors for the Treatment of Glioblastoma”
American Brain Tumor Association Discovery Grant
Summary: OLIG2 is a transcription factor critical to glioblastoma. My analyses revealed that single residues or small foci, called binding hotspots that have typically been the focus of previous transcription factor drug design modeling efforts, do not adequately represent the total active protein surface.  Rather, the transcription factor activation surface appears to include a general, parental pharmacophore and daughter pharmacophores. I identified candidate compound structures from library screens, guided by our parental-daughter pharmacophore criteria, which demonstrated OLIG2 pathway inhibition and potent in vitro and invivo anti-glioblastoma activity. Further study and refinement of the identified active compounds is in progress, which may lead to potent new glioblastoma therapeutics.

 

MARIA J. SAMBADE, PHD
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
Project Title: “Analysis of BRAF Mutant Inhibitor and PARP Inhibitor Combination as a Radiosensitizer Against Melanoma Brain Metastases”
American Brain Tumor Association Discovery Grant in Honor of Nick Festa
Summary: Radiation therapy is an effective treatment against brain cancers, but its mechanism of action- improving its anti-cancer effects while sparing healthy tissue is poorly understood. Radiation is hypothesized to promote cancer cell death through DNA damage. Increasing DNA damage with chemotherapeutics like cisplatin can further improve radiation’s anti-cancer effects. Increases in damage occur by introducing more types of damage or by compromising different DNA repair pathways. The genomic background of the cancer also influences the DNA damage and repair responses. In vitro efforts determined that BRAF mutant melanomas radio-sensitized by BRAF inhibition effect DNA repair processes, including activating PARP1, a DNA repair protein. The hypothesis is that a BRAF inhibitor-PARP inhibitor combination that crosses the blood brain barrier would increase radio-sensitization as compared to single agents. Testing this combination against a melanoma brain metastases preclinical model could generate a new therapy for BRAF mutant melanoma patients. Analysis of collected tissues to examine contributions at the molecular level is ongoing.

 

DEREK A. WAINWRIGHT, PHD
University of Chicago, Chicago, IL
Project Title: “Tryptophan Catabolites in Glioma: Relevance to Diagnostics and Immunotherapeutics”
American Brain Tumor Association Discovery Grant in Honor of Jessica Duininck and Dr. Todd Janus
Summary: To create new potentially effective therapies for GBM, we have turned our attention to the immune system as a high-value medium for causing a patient to spontaneously-reject his/her own tumor. In this investigation, we have collected and analyzed the peripheral blood from brain tumor patients, as well as a high-fidelity transgenic model that faithfully mimics malignant glioma in patients. We were surprised to find that the genetic deletion of an immunosuppressive gene, indoleamine 2,3 dioxygenase 1 (IDO1), resulted in decreased survival in the transgenic glioma model. Moreover this deletion was associated with a normal recruitment of immunosuppressive regulatory T cells (Treg); a pathogenic immune cell subset that we and others have previously shown to be associated with malignant glioma progression. We also identified the gene, IDO2, as a likely candidate that compensates for the loss of IDO1. Thus, a future immunotherapeutic strategy will be to co-inhibit IDO1 and IDO2, simultaneously, since the individual blockade of IDO1 had a limited effect on survival. These data significantly expand our knowledge of primary and secondary (i.e. compensatory) immunosuppression in malignant brain tumors and provides a strong foundation for further pursuit of effective immunotherapies against brain cancer.

 

QIAN XIE, MD, PHD
Van Andel Institute, Grand Rapids, MI
Project Title: “Identifying Genomic Determinants and Signature for MET-Targeted Therapy in Glioblastoma”
American Brain Tumor Association Discovery Grant
Summary: The success of molecular targeted therapy against cancer depends on discovering the tumor driver genes and the molecular determinants that control the pathway activity. The MET pathway activation is a major cause of invasion in GBM tumors. Because MET inhibitors are in clinical trials against GBM, there is a great need to develop patient stratification strategy. Previously we discovered that overexpression of hepatocyte growth factor (HGF), the activating MET ligand, plays a crucial role in determining sensitivity to MET inhibitors. In this study, we intend to expand our knowledge to develop a molecular signature that can be used as a biomarker to identify GBM patients suitable for treating with MET drugs. By analyzing the genomic data sets from GBM patients and those from preclinical tumor models, we found that GBM tumors sensitive to MET inhibitors share common genomic profiles. More importantly, a 25-gene molecular signature was identified that predicted sensitivity to MET inhibitors using patient-derived xenograft models. Our findings are a proof of concept for the use of genomic signatures to identify the suitable patients for MET targeted-therapy in GBM.

KYUSON YUN, PHD
The Jackson Laboratory, Bar Harbor, ME
Project Title: “Predicting Therapy Resistance Based on Cancer Stem Cell Phenotypes”
American Brain Tumor Association Discovery Grant
Summary: In a recent study, we showed that there are three different subtypes of medulloblastoma that spontaneously arise in Ptch+/- model, a widely used model of the SHH subgroup of human tumor. Three tumor subtypes were identified to contain cancer stem cells (CSCs) with drastically different cellular and molecular characteristics. We reported that the one subtype of tumor is propagated by CSCs that are inherently resistant to SHH inhibitors while the CSCs in the other two subtypes are sensitive. We hypothesized that when Ptch tumors are treated with a SHH inhibitor (LDE225), they will give rise to drug-resistant tumors with predictable molecular characteristics. We predicted that drug-resistant GFD subtype tumors will not necessarily contain any new mutations in the SHH pathway since CSCs in this subtype never depended on the SHH pathway. In contrast, we predicted that drug resistant subtype tumors will necessarily acquire mutations within the SHH pathway since CSCs in those tumors depend on the SHH pathway for survival and proliferation.

 

 

TRANSLATIONAL GRANT (2013-2014)
The American Brain Tumor Association Translational Grant is a one year award for pre-clinical research that critically evaluates the diagnostic and/or therapeutic potential of recent discoveries for advancement to clinical application.

 

MARKUS D. SIEGELIN, MD
Columbia University Medical Center, New York City, NY
Project Title: “CP-d/n-ATF5 in Combination with Proapoptotic Agonists as a Novel Potent Treatment for Malignant Glioma”
American Brain Tumor Association Translational Grant in Honor of Naomi Berkowitz
Summary: Our research focused on a new drug compound, called CP-d/n-ATF5, a novel peptide that targets a molecule, called Activating Transcription Factor 5 (ATF5). ATF5 is upregulated in glioblastoma and low-grade gliomas. Interference with ATF5 has shown to induce apoptosis in glioblastoma cells without affecting normal non-tumor cells. Our main efforts consisted of elucidating the mechanisms by which CP-d/n-ATF5 induces apoptosis in glioblastoma cells, which is instrumental for the drug to advance to clinical application. Glioblastoma cells reveal resistance to undergo physiological cell death, leading to their uncontrolled growth and tumor progression. Apoptosis consists of two distinct pathways. Our research indicated that CP-d/n-ATF5 affected both cell death pathways and involves the upregulation of the tumor suppressor p73, the BH3-only protein, PUMA and DR5. PUMA (p53 upregulated modulator of apoptosis) binds Bcl-2/Bcl-xL, two instrumental molecules for the inhibition of programmed cell death, and thereby inhibits their anti-apoptotic functions to induce intrinsic apoptotic cell death. This study has provided us with an in-depth understanding of how CP-d/n-ATF5 affects glioblastoma/tumor cells. These findings will be instrumental and will ease the process for a clinical application of this compound to patients.