The currently funded research of the National Brain Tumor Society is described below as it relates to the two legacy organizations of NBTS.
NBTS is also involved in a number of collaboratively funded research initiatives. For general information on program areas, visit Representative Areas of NBTS Basic & Translational Research.
- 2008 BTS Basic & Translational Research Grant Awards
- Low-Grade Glioma Initiative Research Grant Award
- 2008 NBTF Basic & Translational Research Grant Awards
- Epidemiology Research Grant
- Glioblastoma Multiforme Brain Tumor Research Grant
- Oligodendroglioma Brain Tumor Research Grant
- Caregiver/Quality of Life Brain Tumor Research Grant
Past BTS Grant Recipients
Past NBTF Grant Recipients
2008 BTS Basic & Translational Research Grant Awards
Kenneth Aldape, MD
The University of Texas
MD Anderson Cancer Center
Houston, Texas
Role of YKL-40-beta-catenin signaling axis in GBM progression and radio-resistance
• Brain Tumor Stem Cells
• GBM tumors
• The study investigates the YKL-40 gene. A protein that is produced by this gene is used as a prognostic marker for GBM’s (how well patients will respond to therapy). The gene is also expressed by the newly discovered TIC’s (tumor initiating cells) that are known to self renew.
• Hypothesis: if one silences the YKL-40 gene, then the TIC’s will not be able to form tumors.
(Also see Dr. Kenneth Aldape’s Oligodendroglioma research with funding from NBTF’s Basic/Translational Grant Award)
Matched to James F. Petersen Chair of Research
Azad Bonni, MD, PhD
Harvard Medical School
Boston, Massachusetts
Regulation of glioblastoma pathogenesis by EGFRvIII – STAT3 signaling
• Signal Transduction Pathways
• GBM tumors
• Study looks at how a specific transcription factor---or protein that determines when genes are switched on or off (STAT3) can increase brain tumor growth. STAT3 is involved in proliferation of neural stem cells, angiogenesis (growth of blood vessels that nourish the tumor), invasion, and immunosuppression.
• STAT3 may be an effective therapeutic target. We know how STAT3 suppresses GBM’s under some genetic conditions. This project explores how it participates in the development of GBMs in other genetic conditions.
Matched to Sam Gerson Chair of Research
Nadia Dahmane, PhD
Wistar Institute
Philadelphia, Pennsylvania
Mechanisms regulating stem cell behavior in glioma
• Signal Transduction Pathways
• GBM tumors
• This project studies the role of cancer stem cells in resistance to radiotherapy and chemotherapy. The investigator discovered the gene znf238 that plays a critical role in the Sonic Hedgehog (Shh) signaling pathway (pathways that control cell division for adult stem cells).
• The project will study how the gene affects Shh signaling in healthy neural stem cells and test the hypothesis that znf238 has a tumor suppressor role.
Matched to James F. Petersen Chair of Research
Arti Gaur, PhD
Dartmouth College Medical School
Lebanon, New Hampshire
Role of mir-10a and mir-10b in regulating the pathology of glioblastoma multiforme
• Gene Expression
• GBM tumors
• This study focuses on the control of gene expression that contributes to the malignancy of GBMs. They are looking at 2 particular microRNAs that control the expression of groups of genes. The hope is that they serve as a diagnostic marker (to indicate whether or how fast the tumor is growing) and as a therapeutic target.
• The hope is that these miRNA biomarkers, involved in GBM growth and other human cancers, may be used as a diagnostic marker and therapeutic target.
Matched to Paul Daniel Bogart Chair of Research
Samira Guccione, PhD
Stanford University
Stanford, California
Anti-angiogenic targeted-nanoparticle therapy in canine spontaneous brain tumors
• Experimental therapeutics
• High-grade gliomas
• This project will evaluate a therapeutic approach using nanoparticles that target a cell surface receptor found on brain tumor blood vessels but not normal blood vessels. The approach has been previously demonstrated to be highly effective against brain tumors introduced into mice. However, mouse models are limited because important clinical characteristics of human cancers are lacking in the models.
• This study will test this nanotechnology therapeutic approach on spontaneous high-grade gliomas in dogs which have some of the characteristics lacking in mouse models.
Matched to James F. Petersen Chair of Research
Amy B. Heimberger, MD
The University of Texas
MD Anderson Cancer Center
Houston, Texas
Targeting gliomas with a novel inhibitor of the JAK2/STAT3 pathway
• Experimental Therapeutics
• GBM tumors
• The investigator developed WP1066, an orally delivered STAT3 inhibitor. STAT3 (a protein) functions to both stimulate GBM growth and inhibit the immune system that attacks these same GBM tumors. STAT3 inhibition might simultaneously result in the direct killing of GBM cells and the stimulation of the immune system to attack the same tumor cells.
• The goal of this project is to study agents that inhibit STAT3, having multiple therapeutic effects, and that will ultimately be evaluated for efficacy in a clinical trial. In addition, the goal is to determine if STAT3 is a prognostic biomarker for survival.
Matched to Kayla Wenger Chair of Research
Lawrence Lamb, PhD
University of Alabama at Birmingham
Birmingham, Alabama
Feasibility of T cell immunotherapy for glioblastoma multiforme
• Immunotherapy
• GBM tumors
• The proposed study will explore how a specialized population of white blood cells known as gamma delta T cells might be used for the treatment of glioblastoma multiforme (GBM). Activated gamma delta T cells are able to kill GBM cells in the laboratory. However, in GBM patients these cells have little effect against the tumor.
• This study proposes to determine if gamma delta T cells from GBM patients are defective. If so, it may be possible to use normal gamma delta T cells obtained from healthy donors to treat GBMs in tumor patients.
Matched to Sam Gerson Chair of Research
Duane Mitchell, MD, PhD
Duke University Medical Center
Durham, North Carolina
Clinical development of dendritic cell vaccines targeting brain tumor stem cells
• Immunotherapy
• Astrocytomas
• Dendritic cells are immune cells that process and present foreign antigens to other cells of the immune system, thereby initiating an immune reaction. Brain tumor stem cells express proteins that can act as foreign antigens. An immunotherapy approach in development for a number of tumor types is to introduce tumor antigens into dendritic cells harvested from a patient and return these cells to the patient. These cells would then stimulate the immune system against the tumor.
• This study uses an animal model to test whether dendritic cells expressing brain tumor stem cell protein antigens can stimulate an effective immune response against the stem cells and astrocytomas when returned to the animal. This study can further bolster the rationale for the clinical development of immunotherapy targeted against brain tumor stem cells.
Matched to Billy Grey Chair of Research
John Sampson, MD, PhD
Duke University Medical Center
Durham, North Carolina
Inhibition of regulatory T cell recovery with an IL-2 receptor blocking antibody
• Immunotherapy
• GBM tumors
• We have recently shown that a common virus (CMV) is reactivated in GBM but not in surrounding normal brain tissue. This provides an unparalleled opportunity for tumor-specific immunotherapy. However, brain tumor patients have high numbers of a natural immune cell, Tregs that suppresses the immune attack on the tumor cells. In patients a factor called IL-2 is required to maintain the function and survival of Tregs. In mouse models these investigators have shown that an antibody that blocks the receptor for IL-2 completely eliminates the functional capacity of Tregs.
• The goal of this Phase I clinical trial is to determine if the blocking of the IL-2 receptor with a humanized antibody inhibits the functional recovery of Tregs after temozolomide therapy in patients with GBM.
Matched to Patty Roche Chair of Research
Axel H. Schonthal, PhD
University of Southern California
Los Angeles, California
Blocking autophagy and increasing ER stress to improve therapy of GBM
• Experimental Therapeutics
• GBM tumors
• This study focuses on drug resistance and attempts to increase the effect of chemotherapy, important in patient treatment. Chemotherapy is only effective for a limited time before the tumor recurs. Endoplasmic reticulum stress response (ERSR) may be a factor in drug resistance. The investigator believes that resistance to therapy is due in part to ERSR and refers to it as a potential Achilles heel for brain tumor cells.
• This study will evaluate the ability of several drugs and drug combinations to increase tumor cell endoplasmic reticulum stress sufficiently to overpower the ERSR thereby killing the tumor cells.
Matched to Mickey McDonald Welker Chair of Research
Robert Sobol, PhD
University of Pittsburgh
Pittsburgh, Pennsylvania
PARG regulation of temozolomide induced mitotic checkpoint activation
• Chemoresistance
• High-grade gliomas
• Chemotherapy is effective when it causes overwhelming DNA damage within tumor cells that causes their death. Unfortunately, many tumors have alterations in DNA repair and DNA damage response genes that enable them to repair the DNA damage caused by chemotherapy, making them chemoresistant. The inhibition of one of the proteins involved in this process, PARG, significantly increases tumor cell death following treatment with the chemotherapeutic temozolomide. However, there are 4 different molecular forms of PARG.
• The goal of this study is to evaluate all 4 forms of PARG in order to determine the best way to increase the effectiveness of temozolomide treatment.
Matched to Seth Harris Feldman Chair of Research
Paul Watkins, MD, PhD
Kennedy Krieger Institute
Baltimore, Maryland
ACSVL3-A novel therapeutic target in malignant glioma
• Brain Tumor Cell Membrane Synthesis: Making cell membranes is part of natural cell growth activity. The tumor cells within brain tumors that are rapidly growing synthesize cell membranes at a much higher rate than do normal cells. Research in this area looks at how blocking this process in tumor cells could inhibit tumor growth.
• High-grade gliomas
• This project investigates how the blocking of a natural cell growth activity, the making of cell membranes, could be used to eliminate rapidly growing brain tumor cells. The level of one specific enzyme that activates fatty acid synthesis is extraordinarily high in gliomas.
• This investigator plans to define the role of this fatty acid synthesis enzyme in a well established pre-clinical model of malignant glioma and validate it as a unique therapeutic target.
Matched to Sydney Schlobohm Chair of Research
William Weiss, MD, PhD
University of California, San Francisco
San Francisco, California
Inhibition of P13K and Cdks in glioma
• Experimental Therapeutics
• High-grade gliomas
• This study builds on previous BTS funded work that identified a potential drug molecule that blocks PI3K and kills glioma cells (other drugs block PI3K, but don’t kill the glioma cells). It is important to note that the activation of PI3K is prominent in gliomas and leads to survival of glioma tumor cells.
• This study will evaluate different drug and drug combinations that inhibit PI3K as well as inhibiting other enzymes that drive the cell cycle to determine the most effective combination that kills glioma cells. The hope is to then quickly advance the most effective drug combinations to clinical trials.
Matched to Benjamin Memmott Chair of Research
Hai Yan, MD, PhD
Duke University
Durham, North Carolina
The role of HDMX in GBM oncogenesis and chemoresistance
• Gene Expression
• GBM tumors
• This project studies how a cellular negative regulator of the highly important p53 tumor suppressor is involved in GBM development and drug resistance.
• The investigator discovered a cancer gene called HDMX that negatively regulates p53 signaling (involved in growth and resistance) and will study its role in tumor development and drug resistance.
Matched to Eliza Lorberbaum Chair of Research
Joseph Costello, PhD
University of California, San Francisco
San Francisco, California
Evolution of a hypomethylator phenotype in glioblastoma
· Epigenetics
· GBM tumors
· This project studies a connection between the abnormal activation of a small set of genes that are normally kept silent by DNA methylation, and increased proliferation of GBM tumor cells.
· The goal is to prove or disprove the connection between DNA methylation and abnormally activated set of genes and rapid growth of GBM cells. If successful, a novel dietary approach aimed at increasing DNA methylation might curb tumor growth.
Tom Curran, PhD, FRS
Children’s Hospital of Philadelphia
Philadelphia, Pennsylvania
Generation and characterization of conditional cancer mouse models for atypical teratoic/rhabdoid tumor and choroid plexus carcinoma
· Atypical teratoid/rhabdoid tumor (ATRT) and choroid plexus carcinoma (CPC)
· Mouse Models of Brain Tumors: in genetic mouse models in which genetic engineering is used to create strains of mice that develop human-like brain tumors. In xenograft mouse models, human brain tumor tissue or cell lines are implanted into the cranium of mice. These models are used to study the basic biology of how tumors form and behave, as well as for testing of potential therapeutic approaches.
· ATRT and CPC are highly aggressive pediatric CNS tumors. Many of these tumors are associated with mutations in the Snf5 gene whose function is unknown. This investigator will be establishing a mouse model of ATRT and CPC by generation engineered mice with SnF5 gene mutations.
· An established mouse model will provide the opportunity to further evaluate this association, increase our understanding of how these tumors develop, and enable the testing of potential new therapies.
Juan Fueyo, MD
The University of Texas M.D. Anderson Cancer Center
Houston, Texas
Oncolytic adenoviruses against brain tumor stem cells: The role of autophagy
· Experimental Therapeutics
· High-grade gliomas
· These researchers have developed an oncolytic virus capable of killing brain tumor stem cells and mature glioma cells. An oncolytic virus is a modified virus that is able to infect and kill cancer cells but that does not harm normal cells.
· A goal of this project is to determine the mechanism by which this virus kills glioma cells and tumor stem cells. An additional goal is to develop and evaluate a virus that is further modified to be more effective by its ability to interfere with a cell process involved in normal cell maintenance.
Abhijit Guha, MD, FRCSC, FACS
University of Toronto
Toronto, Ontario
Regional expression and functional role of inhibitors of apoptosis in human GBM
· Apoptosis or Programmed Cell Death
· GBM tumors
· Recurrence is a major challenge in the treatment of patients with malignant brain tumors. In a variety of GBM cell culture and animal models this study evaluates the functional relevance of two proteins (XIAP and Survivin) that inhibit cells from going through the normal process of programmed cell death, thereby protecting the tumor cells
· If either protein plays a significant role in brain tumor survival and growth, inhibitors of these proteins may be tested in these models, to provide a therapeutic strategy to decrease recurrence in these aggressive tumors.
Anita B. Hjelmeland, PhD
Duke University
Durham, North Carolina
Targeting radiation resistance in brain tumor stem cells
· Brain Tumor Stem Cells
· High-grade gliomas
· The study will focus on a protein expressed at high levels in brain tumor stem cells that supports glioma development and resistance to radiation therapy. Drugs that block this protein are currently being evaluated in clinical trials for other diseases.
· The goal of this study is to determine if reduction of this protein in brain tumor stem cells can cause their death and sensitivity to radiation therapy, and ultimately to test drugs in clinical trials that inhibit this protein.
Eric C. Holland, MD, PhD
Memorial Sloan Kettering Cancer Center
New York, New York
Investigating the role of DNA damage response in gliomagenesis and “cancer stem cell” resistance to irradiation
· Brain Tumor Stem Cells
· High-grade gliomas and medulloblastoma tumors
· This is a gene study of chk2’s role as a tumor suppressor. Chk2 is a protein that inhibits cell division and growth.
· The study plans to identify novel characteristics of a protein involved in the repair of DNA damage, the control of tumor growth, and response of tumors to radiation therapy.
Annie Huang, MD, PhD
Hospital For Sick Children.
Toronto, Ontario
Characterization of cell adhesion pathways in childhood sPNET
· sPNET tumors
· Brain Tumor Cell Migration: the ability of brain tumor cells to infiltrate into surrounding brain tissue.
· This study looks at the genetic makeup and expression of genes involved in the control of cell adhesion in sPNETs (supra-tentorial primitive neuroectodermal tumors). The investigator studied the largest collection of these very aggressive pediatric tumors and discovered that molecules involved in maintaining cell to cell contact of adhesion are often altered. Cell adhesion properties contribute to the ability of tumor cells to migrate to other parts of the central nervous system.
· The study hopes to learn more about the cell to cell adhesion mechanism and genetics in sPNETs, and their unique characteristics.
Charles Keller, MD
University of Texas Health Science Center at San Antonio
San Antonio, Texas
Proteasome inhibitor mediated reversal of Shh-driven tumorigenesis
· Experimental therapeutics
· Medulloblastomas
· This is a pediatric study for patients with medulloblastoma that investigates if restoring the balance of components of the Sonic Hedgehog (Shh) signaling pathway using a particular drug will stop the tumor growth.
· This study hopes to lead to a rapid clinical evaluation in pediatric patients since the drug has already been approved for the treatment of leukemia in adults.
Paul Knoepfler, PhD
University of California, Davis
Davis, California
Functional genomics analysis of primitive neuroectodermal tumors
· Epigenetics
· PNETs
· Current treatments for PNETs are limited in their success and often have significant sideeffects. The key to developing safe and effective new treatments is to investigate how PNETs arise.
· This study proposes using a powerful novel approach called functional genomics to uncover chromatin changes in PNETs. This knowledge may serve as the basis for treatments based on reversing such chromatin changes.
Qing Richard Lu, PhD
University of Texas Southwestern Medical Center
Dallas, Texas
Mitotic olig2 expressing cells in glioma formation
· Brain Tumor Stem Cells
· Gliomas
· This study looks at the high recurrence rate of malignant tumors. The investigator has identified a type of multiplying cell that may potentially serve as brain cancer initiating stem cells. A genetic approach is used to eradicate specific stem cells (dividing stem cells expressing Olig2) in a mouse model in order to determine the role of these cells in glioma formation.
· The goal of this project is to determine if the eradication of these stem cells is sufficient to inhibit tumor formation.
Zhimin Lu, MD, PhD
The University of Texas M.D. Anderson Cancer Center
Houston, Texas
Investigation of the mechanism underlying chemoresistance of glioblastoma multiforme to platinum treatment
· Chemoresistance
· GBM tumors
· The problem being studied is drug resistance to platinum compounds the most powerful and widely used treatment for solid tumors. The resistance mechanism is unknown at this point. The study hypothesizes that transcriptional factor c-Jun plays an important role in the resistance of glioma cells to platinum treatment.
· The goal of this study is to determine how platinum causes a drop in levels of c-Jun in glioma cells that are sensitive to platinum, an increase in c-Jun levels in platinum-resistant glioma cells, and to made resistant cells sensitive to platinum by controlling c-Jun activity.
Sadhan Majumder, PhD
The University of Texas M.D. Anderson Cancer Center
Houston, Texas
Novel mechanism of glioblastoma tumorgenesis and therapy
· Brain Tumor Stem Cells
· GBM tumors
· This study focuses on the significant problem of how brain tumor stem cells renew themselves as well as give rise to mature tumor cells. They will study a novel mechanism that controls the self-renewal activity of normal stem cells that is functioning abnormally in glioblastoma stem cells.
· REST, a transcription factor, is a potential target for GBM therapy. Its inhibition might drive glioma stem cells to differentiate into mature glioma cells, thereby eliminating the stem cells that would continuously support the growth of gliomas.
Jeremy Rich, MD
Duke University Medical Center
Durham, North Carolina
Glioma cancer stem cells in tumor angiogenesis
· Brain Tumor Stem Cells
· High-grade gliomas
· The study looks at the mechanisms by which cancer stem cells drive angiogenesis (growth of new blood vessels) in brain tumors and the potential for therapies to stop cancer stem cells from growing. Because normal brain stem cells depend on blood vessels, the study is also comparing the regulation of normal brain stem cells; this is important to prevent new therapies that attack cancer stem cells from affecting the normal brain.
· The hope is that the studies will improve brain tumor treatment by killing cancer cells more effectively and limiting the side effects.
Joshua Rubin, MD, PhD
Washington University
St. Louis, Missouri
Defining the basis of enhanced CXCR4 signaling in brain tumors
· Signal Transduction Pathways
· High-grade gliomas
· The molecule CXCR4 promotes glioma growth. However, the inhibition of CXCR4 would adversely affect normal cells as well as tumor cells. This study will take a deeper look into activity of CXCR4 in glioma cells and normal cells. It appears that CXCR4 affects another family of molecules, the GRKs, differently in normal and glioma cells.
· The goal of this work is to determine whether the GRKs are the switch between normal and abnormal CXCR4 functions. If so, it may provide the opportunity to inhibit CXCR4 in glioma cells in such a way that does not adversely affect normal cells.
2008 NBTF Basic & Translational Research Grant Awards
Epidemiology
The Epidemiology grant offered through NBTF funded research projects focusing on the causes of brain tumors. The science of epidemiology investigates what factors may be associated with a disease (risk factors) and what factors may protect people against disease (protective factors).
Although the literature and the current National Institutes of Health (NIH) research portfolio hold almost no information relevant to the prevention of primary brain tumors, factors that may reduce the risk of primary brain tumors are gradually being identified.
If these isolated results can be replicated and clarified and the underlying biological mechanisms understood, intervention, and prevention strategies may become feasible.
Dora Il’yasova, PhD
Duke University Medical Center
Durham, North Carolina
Individual Response to Low-Dose Radiation
High-dose ionizing radiation is the only known risk factor for glioma. This begs the question does low-dose radiation also increases the risk of glioma? Studying this connection is important because low-dose radiation is commonly used for medical/diagnostic purposes. Medical/diagnostic radiation is often avoidable, giving us an opportunity to prevent needless exposure for a large number of people.
Recent developments in radiation biology show that people respond to low-dose radiation differently. These responses can be pro- or anti-carcinogenic. We believe that a pro-carcinogenic response to low dose radiation may increase the risk of glioma. To test this we will develop an assay (test) that studies individual reaction to low-dose radiation. In clinical practice, this assay could identify high risk individuals for whom medical/diagnostic radiation puts them at significant risk for glioma.
Glioblastoma Multiforme (GBM)
The Glioblastoma Multiforme Brain Tumor Research Grant offered through NBTF legacy organization funds translational research specifically focusing on glioblastoma multiforme.
Karen Aboody, MD
Beckman Research Institute of the City of Hope
Duarte, California
Cellular MRI tracking of neural stem cells: Pre-clinical study
Neural stem cells (NSC) display properties that provide an ideal basis for a novel treatment approach. We propose that these tumor-targeting NSCs serve as a platform for maximizing local concentrations of anti-cancer agents, while minimizing toxicity to normal tissues. This promising approach may overcome the limitations of currently available glioma therapies, and improve clinical outcome.
The study uses iron labeling of the NSCs so that they can be tracked in real-time by cellular MRI to follow their migration and tumor distribution in pre-clinical glioma models. This will allow us to determine optimal treatment paradigms and regimens for planned patient trials. Our therapeutic human HB1.F3.CD NSC line has recently received approval from the NIH Recombinant DNA Committee for use in recurrent glioma patient trials. Successful completion of the study may provide the data necessary to achieve FDA approval to include iron labeling of NSCs to be tracked in real time by cellular MRI. This would provide extremely valuable additional information for this first of its kind human study and optimize planning and design for future therapeutic studies.
Sherri Holmen, PhD
Nevada Cancer Institute
Las Vegas, Nevada
Molecular targeting of survival signaling cascades activated in glioma
Scientists have been developing “targeted” therapies that specifically attack cancer cells while leaving normal cells unharmed. For some cancers, the increased drug specificity and reduced drug-related toxicity has significantly increased survival and improved quality of life for cancer patients.
In the past several years, genes that are altered in GBM relative to normal brain tissue have been found. However, genes that can be productively targeted for effective therapies in patients remain to be identified. The overall objective of this proposal is to better understand the signaling pathways driving cell survival so that new targets can be identified in gliomas. These studies will lead to an increased understanding of the proteins that are altered in this disease and should provide promising opportunities to develop better treatment strategies based on specific molecular targets.
The Nick Gonzales GBM Research Grant
Frederick F. Lang, MD
The University of Texas
MD Anderson Cancer Center
Houston, Texas
Targeting glioma cancer stem cells using bone marrow derived mesenchymal stem cells
Recent studies suggest that malignant gliomas harbor a rare fraction of cells, called Glioma Cancer Stem Cells (GCSCs). It is believed that GCSCs are responsible for tumor recurrence due to their resistance to most therapies. Therefore, the development of strategies that target and eliminate these GCSCs would represent a major advance in the treatment of gliomas.
In this context, we have demonstrated that human Mesenchymal Stem Cells (hMSCs), (stem cells that can be isolated from a patient’s bone marrow) selectively target gliomas after intravascular delivery in human xenograft models. We have also shown that hMSCs engineered to secrete Interferon-β (hMSC-IFN-β) effectively inhibit the growth of gliomas. Although hMSCs are a promising strategy for targeting gliomas, their true potential as therapeutic delivery vehicles would be enhanced by a clear demonstration that hMSCs are capable of targeting GCSCs. However, it is currently unknown whether hMSCs are capable of selectively homing to GCSC or whether hMSCs-IFN-β are capable of eradicating GCSC-derived tumors. This project proposes to answer these questions.
Steven Nimer, MD and Lauren Abrey, MD
Memorial Sloan Kettering Cancer Center
New York, New York
Importance of ETS gene expression in glioblastomas
Glioblastoma is a molecularly heterogeneous tumor; while some pathways for glioma development have been well investigated, it is likely that many other pathways are critical to the formation and aggressive behavior of glioblastoma. The proposed work will look at a group of transcription factors called the ETS family. This gene group is important for cell division, differentiation, angiogenesis and invasion, all of which show evidence of dysfunction in glioblastoma. ETS are over-expressed in many tumors but they have not been studied in gliomas.
The study will focus on two particular factors: MEF and ETS-1. MEF is a novel regulator of stem cell activity; tumor stem cells are increasingly recognized as one of the ways that glioblastoma is resistant to treatment. Understanding mechanisms of tumor resistance to therapy is critical to improve current therapeutic strategies for glioblastoma. ETS-1 is expressed during normal brain development and is an important factor in new blood vessel formation, specifically VEGF regulation, and tumor cell invasion. A hallmark of glioblastoma is neovascularity (the ingrowth of new blood vessels). Recent advances in glioblastoma treatment have capitalized on inhibiting VEGF with drugs such as bevacizumab; it is possible that the ETS-1 may be a critical regulator for glioma related angiogenesis.
Albert Wong, MD
Stanford University
Stanford, California
Developing a recombinant bispecific antibody to target glioblastoma cancer stem cells
Understanding the origins of cancer is one of the most important problems in cancer biology. If the origins can be pinpointed, then therapy can be directed against the cause and not just the entire tumor. The cancer stem cell hypothesis states that a tumor grows from a subset of cells that, like the root of a tree, can give rise to a large tumor but if not eliminated will continue to form tumors. There is now substantial evidence that this hypothesis is true, especially for glioblastoma.
A therapy needs to be directed against the cancer stem cells. To this extent, we have developed an antibody that will specifically recognize the glioblastoma cancer stem cell. We will test this antibody in cell culture models for cancer stem cells to see if it is effective at killing this cell population. Once conditions are optimized, we will extend these studies to an animal model. Our ultimate goal is to develop this agent as a drug for human clinical trials.
Kyusun Yun, PhD
The Jackson Laboratory
Bar Harbor, Maine
A novel biomarker for glioma stem cells and GBM
The long-term goal of this project is to develop tools that can be used to accurately diagnose brain tumors and to develop therapeutics that will block cancer stem cells in gliomas. We identified a gene (S100A6) that is expressed in glioma stem cells. Surprisingly, the abundance of cells expressing S100A6 is a good predictor for glioma grades, distinguishing grade III gliomas from the more malignant grade IV gliomas (GBMs). Because the S100A6 protein can be secreted into blood or cerebrospinal fluid, it may be possible to develop a minimally invasive assay (test) for detecting GBMs.
In addition, because S100A6 is expressed in highly invasive tumors in other organs, it is very likely that S100A6 has an important function in promoting proliferation, invasion, or tumor initiation of cancer stem cells. Hence, we propose to validate our previous findings with a larger set of clinical GBM samples and develop an assay for measuring S100A6 levels in blood. We will also test whether reducing S100A6 protein levels is effective in blocking tumor growth and invasion. Our results will enable more accurate diagnosis of GBMs and also provide a molecular target for new drugs that stop cancer stem cells.
Shichun Zheng, MD
University of California, San Francisco
San Francisco, California
Stem cell polycomb repressor gene targets and temozolomide response in glioblastoma
Many of the changes leading to brain tumors and their resistance to radiation and chemotherapy affect the expression of genes but do not result from alterations of DNA sequence. Such changes are said to be epigenetic, and some are related to very specific alterations of DNA related proteins (histones) that are produced in cancer progenitor stem cells. Identifying the genes that contain these stem cell modifications could help in understanding the basis of resistance to chemotherapies.
Here we plan to scan 18,000 genes in order to construct a map of stem cell genes called Polycomb repressive complex (PRC) target genes within glioblastoma. The tumors are maintained in an animal model and have been extensively characterized for their sensitivity of resistance to temozolomide and ionizing radiation. We will then search for patterns of PRC marked genes that correlate with TMZ response and survival. The study will also examine the expression of genes and chromosomal changes previously linked with drug response. There is great hope that integrating concepts derived from stem cell biology to human cancer therapy will lead to the development of more effective approaches for cancer treatment.
Oligodendroglioma
The Oligodendroglioma Brain Tumor Research Grant offered through NBTF funds translational research specifically focusing on oligodendrogliomas, a type of glioma that develops from cells called oligodendrocytes. These brain cells produce the fatty coverings of nerve cells. This tumor is normally found in the cerebrum, the main part of the brain.
Oligodendrogliomas are relatively uncommon tumors, accounting for no more than 10 percent of primary brain tumors. As such they are an understudied, underfunded tumor type.
Kenneth Aldape, MD
The University of Texas
MD Anderson Cancer Center
Houston,Texas
MicroRNAs in oligodendroglioma
Molecular changes in anaplastic oligodendrogliomas most likely play a role in determining a patient’s response to therapy. One recently described class of molecular markers known to play an important role in cancer is microRNA. MicroRNAs regulate, or control, gene expression.
In this study, we will examine microRNAs as potential biomarkers to predict disease outcome and investigate microRNAs as potential targets for therapy. We will also profile these tumors for messenger RNA to identify key correlations of microRNAs with gene expression changes. We hope the results will provide new insights to the biology of oligodendroglioma and lead to the discovery of new therapeutic targets.
(Also see Kenneth Aldape’s GBM research with funding from BTS’s Basic/Translational Grant Award)
The Michael F. Lewandowski Oligodendroglioma Grant
Andrew Lassman, MD
Memorial Sloan Kettering Cancer Center
New York, New York
Chemotherapy with deferred radiotherapy for treatment naïve anaplastic oligodendroglioma
Controversy surrounds current therapy for anaplastic oligodendroglioma. Radiation can effectively kill tumor cells, but it can also lead to permanent memory loss years later. Chemotherapy can control tumor growth for many years without some of radiation's side effects. However, chemotherapy may not kill tumor cells as effectively as radiation. There are also several chemotherapy drugs available, but it is unclear which of them is best able to kill tumor cells with the fewest side effects. Clinical trials are planned. In the interim, many patients have already been treated and a retrospective study can be done.
We are conducting a multi-institution collaboration to collect clinical data and compare outcomes among more than 1,000 patients treated with various strategies in the USA and Canada in the last 20 years. This is the largest study ever conducted of patients with anaplastic oligodendroglioma. We will determine the most effective treatment strategy in order to determine the most appropriate standard of care for this disease.
Claudia Petritsch, PhD
University of California, San Francisco
San Francisco, California
Defining key genetic and epigenetic alterations in oligodendroglioma cancer stem cells
The discovery of cancer stem cells resistance to conventional therapy has galvanized a search for novel glioma therapies. Successful glioma therapies must target cancer stem cells without harming somatic neural stem cells (an essential source of brain cells). Our research is aimed to characterize the differences between cancer stem cells and wild type adult neural stem cells. This knowledge will allow us to devise a therapy which selectively targets and eradicates cancer stem cells.
We will test if an initial defect in asymmetric cell division makes stem cells more susceptible to additional mutations and therefore capable of inducing tumors. We will also study differences in cancer stem cells on the level of miRNAs, small molecules known to regulate stem cells and cancer. Our long-term goal is to use individual miRNAs as therapeutic targets.
Quality of Life
The NBTF’s Caregiver/Quality of Life Brain Tumor Research Grant funds research that has two components: qualitative/quantitative and interventional.
Brain tumor patients and their caregivers are often confronted with the realization that the disease and its treatment may be accompanied by side effects that have a negative impact on their quality of life. Currently, the majority of research is focused on finding a cure or to prolong life, while critical issues surrounding the ‘quality’ of life like the impact of fatigue, lack of sleep and/or appetite, and depression on patient outcome often go unheeded. Research in this area is crucial to ensure that medical teams can meet the challenge to treat the patient and not just the disease.
Bart Brigidi, PhD
Duke University Medical Center
Durham, North Carolina
Coping skills training for caregivers with primary malignant brain tumors
Caregivers of patients with high grade gliomas exhibit high levels of emotional and physical distress. As a result, the caregivers’ quality of life decreases with prolonged distress due to the threat of the patient’s terminal illness, treatment regimen and neurological changes.
This study evaluates an intervention providing the caregiver with specific coping skills over a six week period. The hope is that this intervention will increase the caregiver’s quality of life.
Mary Lovely, RN, PhD
University of California, San Francisco
San Francisco, CA
Lived experience of a long term survivor with a highly malignant brain tumor
Some patients with highly malignant brain tumors are living longer than previously expected. Extended life seems to be accompanied by neurological disabilities due to the tumor and treatment. Many patients state that life is not the same. This multi-site study is aimed at capturing the experience of living with a brain tumor in patients at least three years after diagnosis. Patients and caregivers will be interviewed. Cognitive testing, symptom and quality of life questionnaires will be administered.
This study will describe the specific challenges of living at least three years with highly malignant gliomas. Interventional studies will follow targeted toward alleviating those challenges.