Kevin Schooler, M.D., Ph.D.Fellow, Pediatric Critical Care
University of Florida
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.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:
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 and schookp@peds.ufl.edu
Donald L. Durden, M.D., Ph.D.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.
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).
Dr. Donald Durden accepts his Research Grant award from (l) Lisa Mitchell, BTFC Secretary, and Mary Campbell, Executive Director
Erwin G. Van Meir, PhD, Professor of Neurosurgery and Hematology/OncologyLay 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 at http://www.neurosurgery.emory.edu/BTP/research.htm or http://www.neurosurgery.emory.edu/FacultyVanMeir.htm