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We have had an exciting 2009 and 2010. Please read below about what is occurring in Brain Tumor Research.
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2009/2010
July 2010: BTFC is not currently accepting research grant applications. Check back for future opportunities.
Congratulations to our “2010 BTFC Research Scholar Award” Recipients
BTFC is proud to announce its 2010 Research Scholar Award recipients:
 Tobey J. MacDonald, MD, Principal Investigator
Associate Professor Pediatrics
Director, Pediatric Neuro-Oncology Program
Emory University School of Medicine
Senior Brain Tumor Foundation for Children Research Scholar Award - $50,000
Laymen’s Summary
Title: Preclinical investigation of novel agents against the PDGFR-Rac1-Pak1 signaling pathway in the SmoA mouse medulloblastoma model
The specific aim of this project is to test a combination of novel drug treatments derived from the previous and ongoing experimental laboratory studies of the Principal Investigator (PI) in a mouse model of medulloblastoma for the purpose of identifying an effective therapeutic strategy for future development for human pediatric clinical trials for this disease.
In 2001, the PI discovered that a protein that helps tumor cells to survive and grow, called platelet-derived growth factor receptor (PDGFR), is abundantly made by medulloblastomas that have shown evidence of tumor spread to other parts of the brain and central nervous system (MacDonald et al., Nature Genetics 2001). We showed that PDGFR can initiate and propagate a signal inside the medulloblastoma tumor cell by linking it to other proteins inside the cell and that this signal serves to control the movement and growth of the cell. More recently, in a follow-up study of this previous work, the PI showed that blocking the activity of the PDGFR protein with a drug called Imatinib mesylate or Gleevec, which is currently used for the treatment of specific types of leukemia, can prevent medulloblastoma cells from moving from one area to another (Abouantoun et al., Molecular Cancer Therapeutics 2009). Ongoing studies in the PI’s lab now show that treating medulloblastoma cells with other drugs, such as Tris-dipalldium (Tris-DBA), that target proteins further along the signaling pathway generated by PDGFR, called Ras, Rac1 and Pak1, in addition to Gleevec not only prevents the cells from moving but also causes the tumor cells to die. In this study, we plan to treat mice that have been genetically engineered to spontaneously develop medulloblastoma by 2 months of age, in which one-third will develop evidence of tumor spread by 4 months and all will succumb to their disease by 6 months of age, with a combination of drugs that target PDGFR-Rac1-Pak1 to see whether this treatment will prevent the growth and spread of medulloblastoma and ultimately improve survival compared to untreated control mice. All of the drugs to be tested in the medulloblastoma model have already been shown to be safe and well-tolerated in mice. If the preclinical testing is successful in achieving these objectives, then the future plan would be development of human pediatric clinical trials testing the safety and efficacy of these drugs in patients with medulloblastoma.
The preclinical testing studies proposed would be the lead experiments for the pediatric brain tumor innovative translational research endeavor that I have been recruited to direct and thus would be vital for jump-starting the program with respect to new areas of research funding, national recognition, and faculty recruitment to further build the pediatric arm of the scientific research for brain tumors at Children’s Healthcare of Atlanta/Emory University.
We anticipate that the total time of the project will be one year for the study of 40 mice (two cohorts of 10 control untreated mice and 10 drug-treated research mice, 1st cohort treated at 1 month of age and second cohort at 3 months of age) injected with the two drugs at the time points indicated and followed for 6-9 months for disease outcome. An abstract of the preliminary work is being presented October 1, 2009 at the Pediatric Brain Tumor Foundation-sponsored pediatric neuro-oncology meeting in Asheville, NC. No funding is currently in place for this specific project, but if funded, further NIH R21 or equivalent funding will be pursued.
To learn more about Dr. MacDonald, visit http://www.choa.org/default.aspx?id=8740
 Anne G. Gilg, Ph.D.
Assistant Professor
Medical College of Georgia Cancer Center
Junior Brain Tumor Foundation for Children Research Scholar Award - $25,000
Layman’s Summary
Pediatric brain tumors have been shown recently to contain a small sub-population of cells which are highly tumorigenic and inherently resistant to chemotherapy and radiation therapy. These cells have been termed “cancer stem cells”, “cancer progenitor cells”, and “tumor initiating cells”. These cancer stem-like cells (CSLC) contribute to tumorigenesis and therapy resistance and most likely account for tumor recurrence. We have established that a key factor involved in therapy resistance is hyaluronan, a polysaccharide that is a major component of the pericellular matrix surrounding glioblastoma cells in vivo. Hyaluronan interacts with its major receptor, CD44, and regulates major cell signaling pathways and drug effluxers. The role of hyaluronan signaling in the treatment-resistant CSLC population is unknown. The objective of the proposed studies is to determine if small fragments of hyaluronan, hyaluronan oligomers, by interfering with constitutive hyaluronan /CD44 interactions, can abrogate drug and radiation resistance in glioma CSLC. We will isolate CSLC from surgical glioblastoma tissue as tumor spheroids which have been shown to preserve malignant and therapy resistant properties and are a reliable means to enrich CSLC from glioblastomas. Once isolated, in our first aim we will test cells derived for these spheroids against chemotherapeutics and determine if hyaluronan oligomer treatment will sensitize the cells. Our second aim will be to determine if hyaluronan oligomer treatment is radio-sensitizing to this same population of cells. Our goal is not to determine the “stemness” of these cells but rather to focus on the therapy resistance preserved by the spheroid culture technique. This approach will allow us to examine the efficacy of hyaluronan oligomer on a larger number of patients than would be possible using in vivo xenograft methods. Results of these studies will be beneficial in determining which chemotherapy drugs can be best combined with hyaluronan oligomer therapy and whether radiation dosages can be minimized with the addition of hyaluronan oligomer thereby reducing negative side effects.
As a newly appointed junior faculty member in the Cancer Center at the Medical College of Georgia, this award would help to support my research in developing hyaluronan oligomers as therapy for pediatric brain tumors. This research is currently funded by start-up funding of Dr. Bernard Maria. The results of the proposed studies will be prepared as a manuscript for publication in a top tier peer-reviewed cancer journal (Cancer Research, Clinical Cancer Research, etc.). In addition, this work will be presented at a national meeting (Society for Neuro-oncology, Fall 2010). Finally, these data will be used to submit an NIH R01 application.
Given our preliminary data on rat glioma and U87 human glioma both in vitro and in vivo we anticipate that hyaluronan oligomers will indeed sensitize CSLC to chemotherapy and radiation. These findings will be instrumental in the design of pre-clinical animal studies in preparation for a clinical trial of HA oligomers as therapy for pediatric brain tumors.
To learn more about Dr. Gilg, visit http://webapp.mcg.edu/PROD/ifl.viewfac?CGIemplid=017361
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2007/2008
RESEARCH IS CRITICAL
Learn about current "Junior and Senior Brain Tumor Foundation
for Children Scholar Award" funding opportunities. |
Research Funding is important to us at the Brain Tumor Foundation for Children and we have funded many projects over the years. In 2007, the Board of Directors voted to designate all proceeds from William’s Walk & Run Presented by Elekta to research funding. Over $90,000 was raised and the Board voted to add $35,000 more in order to fund a total of $125,000 in “Brain Tumor Foundation for Children Research Scholar Awards.” The following awards were presented at the Foundation’s 25th Anniversary Fundraising Event on Sunday, March 30, 2008 at the Atlanta History Center. |
Kevin Schooler, M.D., Ph.D.
Fellow, Pediatric Critical Care
University of Florida
Junior Brain Tumor Foundation for Children Research
Scholar - $25,000
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Dr. Schooler is an outstanding clinician-scientist who is
passionate and committed to brain tumor research.
Dr. Schooler’s $25,000 grant will help him continue his work on the following project:
| Laymen’s Summary
Transglutaminase 2 (TG2) is a protein that is widely expressed in this human body. One of its functions is to cross-link extracellular components and function as a barrier to tumor spread. By an unknown mechanism, TG2 expression also controls sensitivity to the chemotherapeutic drug doxorubicin. My lab has recently found that TG2 expression is commonly shut off in breast tumors by a process termed “epigenetically silencing“ and that this is associated with doxorubicin and alkylator sensitivity in this tumor type. Preliminary and ongoing studies conducted by me in the Brown lab clearly indicate that TG2 is also silenced in adult and pediatric brain tumors as well. This leads me to hypothesize that TG2 expression is a potential marker for chemotherapeutic drug sensitivity in brain tumors and an ideal target for the development of new drugs that interfere with TG2 activity.
My study has two Specific Aims: 1) I will examine the role that TG2 plays in glioma cell sensitivity to a panel of drugs often used in the treatment of brain tumors. Using various tests that examine drug sensitivity (short-term drug toxicity, long-tem cell survival, and effects on cell growth kinetics), I will determine if TG2 is a general regulator of chemosensitivity in engineered glioma cells that either express TG2 of do not, or if this protein confers sensitivity to only certain drugs. 2) I will examine which function and which cellular location of this multifunctional protein is responsible for its ability to confer chemotherapeutic drug sensitivity. Using various TG2 mutants and molecular targeting approaches, we will express functional and non-functional forms of TG2 that target this protein to the nucleus, cell membrane and for cell export. Following this, I will test these cells for alkylator sensitivity to determine which location of TG2 is important in controlling its effects on chemosensitivity. These studies are a required starting point as I begin to develop drugs to block TG2 activity.
The long-term goal of my research is to optimize treatment of brain tumors arising in children. As an outcome of these studies I will understand the spectrum of drugs for which TG2 expression influences cellular sensitivity. This information will be clinically useful in treating brain tumors by providing clues as to appropriate treatment options. I will also have a solid foundation of information necessary to develop drugs that interfere with TG2 function since such drugs will predictably “boost” the effectiveness of tumor treatment.
I am currently a Fellow in the Dept. of Pediatrics at University of Florida and have approximately 18 months left in my training program. Once done with my training, I plan to pursue a career as a clinician/scientist focused on pediatric cancer. I have recently been awarded a Fellowship from the Univ. of Florida College of Medicine that will give me a full year of release time from clinical duties. The funding through this Junior Brain Tumor Foundation for Children Scholar Award will provide me with the necessary funds to purchase supplies, reagents and other expenses associated with conducting this research. My plan is to use this BTFC funding to generate publications and preliminary evidence that will be crucial to compete for federal funding sources when I begin my independent career.
During the last year in the Brown lab I have documented using various biochemical and molecular biological approaches that TG2 is epigenetically silenced in adult and pediatric brain tumors. It is likely that I will present this work at a national meeting within a year and, at this time, have a manuscript finished that will be submitted to a top-tier cancer journal (Cancer Research, Oncogene, Carcinogenesis, etc).
You can learn more about Dr. Schooler and his work at www.peds.ufl.edu.
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Donald L. Durden, M.D., Ph.D.
Scientific Director, Basic and Translational Research
Aflac Field Force Children’s Chair for Experimental Therapy
Aflac Cancer Center and Blood Disorders Service
Children’s Healthcare of Atlanta
Professor of Pediatrics, Emory University School of
Medicine Winship Cancer Institute
Senior Brain Tumor Foundation for Children Research
Scholar - $50,000
Dr. Donald Durden accepts his Research Grant award from (l) Lisa Mitchell, BTFC Secretary, and Mary Campbell, Executive Director
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Laymen’s Summary
This project will evaluate a novel small molecule prodrug P1-3 kinase inhibitor, SF1126 for GBM therapeutic activity. The proposal will establish novel pharmacodynamic methods to monitor response to this therapeutic agent in vivo. We will translate this information to the bedside.
Nontechnical Summary:
Malignant brain tumors (high grade gliomas, HGG) represent one of the most frequent neoplasms diagnosed in young adults and children. HGG represent a significant challenge to the pediatric or adult neurosurgeon and neurooncologist. This group of tumors share common features amongst them- an addiction to a certain signaling pathway which makes these tumors proliferate and resist current therapy. We view these tumor specific communication networks as the best target for antitumor therapeutics at this time. The target is termed “P1-3 kinase” and we seek to develop inhibitors of this molecule and test them in animal models of human HGG. One such drug developed by Dr. Durden and his laboratory has been approved by the FDA for human testing and we are currently going after other novel drugs using sophisticated computer based drug screening methods. Using these computer based searches we have found a number of potential new drugs which we hope to test and eventually develop for glioma therapy in the near future. Dedicated research time is needed to test these potential therapies. The research findings can dramatically improve therapies for patients battling malignant brain tumors. In addition, the findings of our research only serve to attract more scientists to the Aflac Cancer Center to pursue cures for all types of cancers. Currently Dr. Durden and his team have funding from Aflac, the NIH, the Georgia Cancer Coalition and the Goldhirsh Foundation Award. The opportunity of the Senior Brain Tumor Scholar Award centers around the fact that the award guarantees protected time for Dr. Durden to spend conducting this vital research into developing new drug therapies for children and young adults with brain tumors. Most recently Dr. Durden was published in the January 1st issue of Cancer Research about his findings and the future research promise of his lab.
Project Summary:
The overarching goal and scientific focus of our proposal will be to employ novel drug discovery methods to discover new P1-3 kinase inhibitors to malignant glioma therapy. Malignant diffuse gliomas are the most frequently diagnosed in brain tumor patients. These tumors carry a poor prognosis and are associated with an angiogenic phenotype. Over the past six years our laboratory and other groups have defined the role of PTEN and P1-3 kinase in glioma angiogenesis and performed experiments which provide “proof of principle” that P1-3 kinase inhibitors have antiglioma activity in vivo. The P1-3K pathway plays a central role in glucose uptake and metabolism, response to nutrients, cellular proliferation, cell cycle progression, viability, motility, invasion, neovascularization, and metastases. Hence, we term the P1-3 kinase-PTEN as an “intercept node” for the control of multiple important signaling pathways. Inhibition of the P1-3K pathway thus has the potential to improve the clinical outcome for brain tumor patients. This project details the rationale behind and the plans to evaluate multiple small molecule inhibitors selectively targeting the P1-3K signaling pathway in GBM. We seek to utilize our well established glioma systems to further evaluate our first P1-3 kinase inhibitor, SF1128 in preclinical models for GBM and to apply these animal and cell based models to our new inhibitors currently under study (3 lead compounds currently undergoing, SAR, lead optimization and derivitization).
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Erwin G. Van Meir, PhD, Professor of Neurosurgery and Hematology/Oncology
Director, Winship Cancer Institute Brain Tumor and Molecular Pathways and Biomarkers Programs
Emory University School of Medicine
Senior Brain Tumor Foundation for Children Research
Scholar - $50,000
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Lay Summary of the Proposed Research
Oxygen is required for the survival of every cell in the human body. It is delivered to cells through a large number of blood vessels that perfuse every major organ. However, rapidly expanding tumors soon outgrow the capacity of existing blood vessels to deliver oxygen. Thus, central regions of tumors are deprived of oxygen, a condition known as hypoxia. To survive hypoxia, tumor cells modify their metabolism, and induce growth of new blood vessels in the tumor, a process termed angiogenesis. A central molecule that is responsible for these adaptive processes is Hypoxia Inducible Factor-1 (HIF-1). Therefore, inactivating HIF-1 is expected to cause hypoxic tumor cells to die. Indeed, there is a large body of experimental evidence to support this theory. Our laboratory has developed a new class of natural product-like drugs that efficiently inhibit the activity of HIF-1 in tumor cells. Here we propose to perform pharmacological evaluation of one of these molecules, KCN1 and test its ability to reduce the growth of human pediatric brain tumors (glioma and medulloblastoma) in animal models. These studies are a very important step towards a potential clinical use of KCN1 for the treatment of brain tumors in pediatric patients. This new drug may prove a valuable addition to the scarce arsenal of therapies available today for the treatment of brain tumors in children.
You can learn more about Dr. Van Meir and his work here.
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