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PLGA Funded Research The mission of the Pediatric Low Grade Astrocytoma Foundation, is to fund research projects that will help develop a better understanding of JPAs, Fibrillary Astrocytomas and other forms of Pediatric Low Grade Astrocytomas with a goal of developing targeted therapeutics to treat PLGAs with substantially better outcomes and lower toxicity. Dana-Farber Cancer Institute’s Pediatric Low Grade Astrocytoma Program May 2007 A $2.0mm grant provided by families associated with the Pediatric Low Grade Astrocyoma Foundation created a new program at Dana-Faber to focus on low grade tumors and to discover new and improved targeted therapies that don’t risk impairing children’s bodies and minds. The PLGA Program – under the direction of Charles Stiles, PhD, and Mark Kieran, MD, PhD – will draw resources, including personnel and technology, from Dana-Farber’s pediatric neuro-oncology program, the Department of Neurobiology at Harvard Medical School, Children's Hospital Boston, and the Broad Institute of MIT and Harvard. In addition to many individual projects within the LGA program, the flagship project of this program will analyze 50-60 JPA and Fibrillary Astrocytoma samples looking for mutated genes by utilizing SNP arrays and a new technology, Shape–based Gene Sequencing. The goal of the flagship project for the LGA Program is to identify a drug-susceptible target for low grade astrocytoma within a five-year period of time. To read the press release, click here. To learn more about the DFCI PLGA Program, click here. Dana-Farber Cancer Institute, Boston, MA The following two projects were funded through a gift made by the Jacob Gainey Research Fund in Fibrillary Astrocytomas and Low Grade Gliomas. Principal Investigator Dr. Mark Kieran, MD,PhD Immunohistochemical Analysis: In 2005, immunohistochemical analysis of 78 pediatric brain tumor samples led to the development of data for clinical trials for two promising biological therapies - AZD2171 and CCI779. In fact, a Phase I clinical trial of AZD2171 in children with recurrent or progressive central nervous system tumors was recently opened through the Pediatric Brain Tumor Consortium, and a second trial with this agent has been proposed for children specifically with recurrent low-grade gliomas. Gene expression studies of “gene chips” built from paraffin-embedded archival samples of LGG tumors. The preliminary genomic study includes 288 samples, with both type 1 and type 2 low-grade gliomas represented. All samples are archival samples from a patient population representing 20 years of clinical history and therapy outcomes. The goal of the pilot study is to reveal which genes in the LGG tumors are more or less active (up- or downregulated) compared with normal brain tissue. Dr. Mark Kieran, in conjunction with the Broad Institute at MIT (and with Todd Golub, M.D., along with a dedicated Pediatric Neuro-Pathologist) initiated a novel method of paraffin section RNA analysis. The Broad Institute will use a new methodology to analyze a total of 96 samples simultaneously, a methodology that requires analysis within 48 hours of cutting. Three (3) pathologists will coordinate with the Broad Institute to carry out this process. If we determine genes that are either up- or downregulated, and the genomic changes are relevant – in other words, they are directly linked to tumor development and growth – we will stain tumor samples for the proteins produced by the genes highlighted in the expression studies. University of California, San Francisco PLGA Grant Targeting Cancer Stem Cells in Pediatric Fibrillary Astrocytoma Principal Investigators David Rowitch MD, PhD; C. David James PhD; Graeme Hodgson PhD September 2007 A $500,000 grant was awarded by the Pediatric Low Grade Astrocytoma Foundation in honor of Jake Gainey to study pediatric fibrillary astrocytomas. The ultimate goal of this proposal is to change the landscape of pediatric grade II glioma (fibrillary astrocytoma) research by investigating the biological regulation of cancer stem cells. In this proposal, we will focus on ideas that are “short-term”: that is, likely to yield new insights within two years, as based on our use of data already in hand that provided clues to low-grade glioma biology: · We will develop animal models of low-grade astrocytoma that lack the tumor suppressor gene “p53,” which is the only recognized genetic lesion in human low-grade gliomas. · We will model interactions of p53 and the “Sonic Hedgehog” growth factor pathway that has recently been implicated in low-grade glioma development. · We will incorporate a cancer stem cell perspective throughout these studies and will target mutations specifically to “Olig2” – expression progenitor cells in the brain and in astroctytic tumors. Drs. Rowitch and Charles Stiles (at Dana-Farber Cancer Institute in Boston) recently determined that Olig2 is a key market of the stem cell component of adult gliomas, and our preliminary evidence suggests an equally important role of Olig2 in pediatric low-and high-grade astrocytomas. · Finally, we will conduct a comprehensive analysis of the distinct genetic mutations that underlie pediatric low-grade astrocytoma formation. The results of this analysis will facilitate the identification of effective, targeted therapeutics for treating these tumors through the refinement of animal models for testing novel therapeutics. We recognize, however, that in the long-term an extensive and multifaceted approach will be needed to definitively address the critical questions of: (1) What exactly caused low-grade pediatric astrocytomas to form? (2) How can they best be treated using novel chemotherapeutic agents? (3) How can these drugs best be delivered to the tumor for maximum clinical effects and minimal whole body side effects. For more information on this grant, click here. 2008 Pediatric Low Grade Astrocytoma Grants Funded We would like to thank the Brain Tumor Society (BTS) Boston for their support of the following grants through the Pediatric Low Grade Glioma Initiative. The following grants are made possible through the collective efforts of the riders from Team Jake, Team Samantha, Team TJ and Team Lucy in the Brain Tumor Society’s 14th annual Ride for Research which raised over $750,000 for dedicated pediatric low grade astrocytoma research. We would like to express our sincere gratitude for the overwhelming support and generosity of all the riders and donors who made the 2008 Ride for Research such a great success. A Phase II Study of RAD001 for Children with Chemotherapy Hemotherapy-Refractory Progressive Symptomatic Low-Grade Gliomas Principal Investigator: Mark Kieran, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts Low-grade gliomas are the most common brain tumor in children. While a portion of patients are effectively cured with surgery alone, for a significant majority, especially those without neurofibromatosis type 1, recurrences are common. These patients often require repeated resections, chemotherapy and radiation therapy. The damage caused by these therapies has a significant impact in the lives of these children. More targeted and less toxic therapies in this population are therefore required. An important pathway that has been implicated in pediatric low-grade gliomas is mTOR, a central relay site within the cell that when activated, results in increased proliferation, cell migration and angiogenesis. Our preliminary work has demonstrated the presence and activation of this pathway in LGGs samples from children without NF1. RAD001 is a new oral mTOR inhibitor that has demonstrated excellent inhibition of this pathway at clinically achievable doses. The drug is exceedingly well tolerated and is currently used to reduce the risk of solid organ transplant rejection. We are now proposing a formal multi-institutional clinical trial of RAD001 in non-NF1 children with recurrent or progressive LGGs after standard treatment. Targeting the Hedgehog Pathway in Pediatric Low-Grade Glioma Principal Investigator: Michael K. Cooper, MD, Vanderbilt University Medical Center, Nashville, Tennessee The intractable nature of gliomas to current chemotherapies and radiation underscores a tremendous need for improved interventions. A recent advancement in our understanding of malignancies have been the identification of a rather small population of cancer cells that are critical for maintaining the growth of the entire tumor. These cancer stem cells appear to be resistant to the conventional chemotherapy and radiation treatments. However, another major advancement has been the recognition that some of the same signaling pathways that regulate the growth of the stem cells during embryonic development also regulate cancer stem cells. One of these developmental pathways is called the Hedgehog signaling pathway. In malignancies of the skin, lung and intestine for example, it has been demonstrated that Hedgehog signaling is required for their growth. In our previous work, we have identified compounds that inhibit Hedgehog signaling and determined that the Hedgehog pathway is activated in stem cells in some types of adult gliomas. Thus the inhibition of Hedgehog signaling in certain glioma subtypes may target a critical tumor cell population in a pathway-specific manner. In this proposal, we seek to better define the pediatric glioma subtypes in which the Hedgehog pathway is activated and to determine whether the delivery of Hedgehog inhibitors will halt the growth of these human gliomas in an animal model. If successful, these preclinical findings will constitute an important component for developing a novel therapeutic strategy for malignant gliomas and a basis for patient selection. Development of Clinically Relevant Orthotopic Xenograft Mouse Models of Childhood Low-Grade Glioma from Primary Tumor Tissues Principal Investigator: Xiao-Nan Li, MD, PhD, Texas Children’s Hospital-Baylor College of Medicine, The goal of this project is to develop and characterize a panel of primary tumor-based orthotopic xenograft mouse models of pediatric low-grade glioma for broad distribution and use in understanding the biology and testing novel therapies. Using our surgical protocols that have successfully achieved greater than 70% (20 models from 28 specimens) tumor take rate in malignant pediatric brain tumors, we aim to develop 4-5 transplantable orthotopic xenograft models through direct implantation of 20-25 fresh surgical specimens of low grade gliomas into anatomically matched locations in mouse brains. Detailed characterization of the xenograft tumors will be performed to make sure they faithfully replicate the biology of the original patients tumor, and to identify all genetic abnormalities. We will also examine if cancer stem cells play a role in determining the xenograft forming capabilities by correlating cancer stem cell frequencies in patient tumors with their tumor take rate. Sine these xenograft lines are patient specific, each derive from distinct pediatric patients, and sustained through serial subtransplatations in mouse brains and long-term cryopreservation, we will be able to provide a large cohort of clinically relevant animal models, on demand, to facilitate marker and target identifications and expedite the development to effective therapies. Identification of the Molecular Signature of Progressive JPA Principal Investigator: Elizabeth Maher, MD, PhD, University of Texas Southwestern Medical Center, Dallas, Texas Pilocytic astrocytomas (PA), the most common childhood brain tumor, is classified into 2 groups, those that are resected and do not recur (“non-progressors”), and those that recur early and need further treatment, “progressors.” There is little that distinguishes these patients at diagnosis, a fact which leads to uncertainty regarding the need for further treatment on the part of the physician and uneasiness and worry about the long-term outcome for their children on the part of the parent. A large part of pediatric PA patients has been followed at UT Southwestern Medical Center over the past 25 years and a database of clinical information linked to a tissue repository containing tumor samples from most of the patients has been amassed. Over the past year we have initiated a pilot study of 32 patients (16 progressors, 16 nonprogressors) to generate comprehensive molecular profiles of their tumors with the goal of identifying specific distinguishing genetic altercations in these groups. Exciting preliminary data shows distinct differences, lending confidence to the assertion that the studies proposed here will identify novel markers that can predict progressive disease and, equally important, identify novel targets for new drug development for this important childhood disease. Identification of the Molecular Signature of Progressive JPA Principal Investigator: Elizabeth Maher, MD, PhD, University of Texas Southwestern Medical Center, Dallas, Texas Pilocytic astrocytomas (PA), the most common childhood brain tumor, is classified into 2 groups, those that are resected and do not recur (“non-progressors”), and those that recur early and need further treatment, “progressors.” There is little that distinguishes these patients at diagnosis, a fact which leads to uncertainty regarding the need for further treatment on the part of the physician and uneasiness and worry about the long-term outcome for their children on the part of the parent. A large part of pediatric PA patients has been followed at UT Southwestern Medical Center over the past 25 years and a database of clinical information linked to a tissue repository containing tumor samples from most of the patients has been amassed. Over the past year we have initiated a pilot study of 32 patients (16 progressors, 16 nonprogressors) to generate comprehensive molecular profiles of their tumors with the goal of identifying specific distinguishing genetic altercations in these groups. Exciting preliminary data shows distinct differences, lending confidence to the assertion that the studies proposed here will identify novel markers that can predict progressive disease and, equally important, identify novel targets for new drug development for this important childhood disease. 2007 Pediatric Low Grade Astrocytoma Grants Funded We would like to thank the Brain Tumor Society (BTS) Boston for their support of the following grants through the Pediatric Low Grade Glioma Initiative. The following grants are made possible through the collective efforts of the riders from Team Jake, Team Samantha, Team TJ and Team Lucy in the Brain Tumor Society’s 13th annual Ride for Research which raised over $1.1mm for dedicated pediatric low grade astrocytoma research. We would like to express our sincere gratitude for the overwhelming support and generosity of all the riders and donors who made the 2007 Ride for Research such a great success. The Biologic and Prognostic Role of Replicative and Oncogene Induced Senescence in Pediatric Low Grade Gliomas. This study will study why some PLGA tumors stop growing. Using this alternative research strategy, we will build on previous results that demonstrated that a mechanism that controls tumor growth arrest, defined as senescence, predicts outcome in PLGA. With the collaboration between three of the leading pediatric neuro-oncology centers in North America, we plan to expand our preliminary findings and to determine the pathways that control senescence in PLGA. Upon completion of this project, we will be able to better predict which patients are unlikely to have tumor progression (and can thus be spared from current toxic therapies). We will uncover novel targets as therapeutic options for PLGA. Furthermore our findings will provide a framework for a new understanding of astrocytoma behavior in children. Molecular Prognostic Markers for Low-Grade Gliomas. This study will apply the prognostic markers in childhood high-grade gliomas to analyze low-grade gliomas. We will evaluate a series of hypothesis-based markers linked with glioma progression in previous studies, such as MGMT status, proliferation index and genetic alterations. These results would be amenable to comparison with results from high-throughput allelotyping. We will evaluate 100 favorable-risk" (e.g., grossly resected) tumors in parallel with 100 "higher-risk" (unresectable brainstem and diencephalic) lesions. This analysis should have s sufficient statistical power to identify meaningful prognostic associations, and would provide new insights into biological correlates of prognosis in pediatric gliomas and therapeutic targets to improve the chances of curing these tumors. Development of Permanent Juvenile Pilocytic Astrocytoma Cell Lines for Preclinical Trails. This study will investigate different methods to immortalize JPA primary cells which have limited growth potential. Cell culture method will involve the expressing of telomerase gene into JPA primary cells with limited growth potential. Over-expression of telomerase has previously shown to increase the life span of human cells. Additionally, we will attempt to inject fresh JPA tumor tissue into SCID mice which are severely immunodeficient to investigate whether JPA tumor cells can be propagated inside the brain of the SCID mice. The successful development of these resources will allow us to perform various pre-clinical trials of various therapeutic strategies in the future. Controlling Pilocytic Astrocytoma Growth: Effects of location, age and Telomerase. This study will evaluate three growth characteristics of JPA that might offer clues for research. First, JPA is primarily a disease of childhood. Second, JPAs behave differently when they occur in different parts of the brain. Third, JPAs grow slowly and often stop growing spontaneously, possibly because JPAs cannot bypass the 'biological clock' that stops non-cancer cells from growing indefinitely. We will implant JPA cells taken from children undergoing surgical removal of their tumor into the brains of mice. We will determine if these cells grow preferentially when they are implanted into the brains of very young mice in places that correspond to the original location of the tumor in the patient, and if so, why. We will also put telomerase, a gene that bypasses the 'biological clock' into JPA cells and see if this allows tumor growth in mice brains. This project could identify proteins or genes that are important for JPA growth that could be used as targets for drugs or therapies to cure JPA. Identification of Key Genetic and Growth Control Pathway Changes in Pediatric Fibrillary Astrocyoma (PFA) that Represent Potential Molecular Targets for Therapuetic Intervention. This study represents a collaborative project that builds upon the 2006 BTS-funded project focused on juvenile pilocytic astrocytomas (JPAs). The 2006 project boasted the first truly comprehensive genomic, genetic and proteomic analysis of JPAs. This year’s project will focus on pediatric fibrillary astrocytomas (PFA) as it continues to employ multiple complementary highthroughput technologies to identify key molecular genetic changes (DNA, RNA and protein) and growth control pathways that represent potential molecular targets for future therapeutic drug design. This approach, leading to “targeted therapeutics,” has had great success in a number of adult cancers. Unfortunately, unlike some of the other common childhood tumors, PFA has not been subjected to the same rigorous and comprehensive molecular analysis that constitutes the necessary first step for the development of targeted therapeutics. No single study has analyzed a sufficiently large enough sample size, and more importantly, no investigation has concurrently studied the DNA, RNA and corresponding protein expression of each individual tumor to make definitive and statistically valid conclusions regarding the molecular basis of PFA. 2006 Pediatric Low Grade Astrocytoma Grant Identification of Key Genetic and Growth Control Pathway Changes in JPA that Represent Potential Molecular Targets for Therapuetic Intervention.
A collaborative project conducting the first truly comprehensive genomic, genetic and proteomic analysis of JPAs. The project is being conducted by Dr. David Gutmann and Dr. Tobey MacDonald. This project will apply cutting edge bioinformatics techniques to proven genetic, genomic and proteomic analyses which have helped lead to the development of "targeted therapeutics" in a number of adult cancers.
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