To raise the awareness and funds necessary
 to overcome pediatric brain tumors and to help
 the children and families affected by them.

Funded Research

The Matthew Larson Foundation for Pediatric Brain Tumors awards annual grants through a competitive application and review process.  Each year submissions are thoroughly evaluated by the Medical Advisory Committee and written recommendations are submitted to the Board of Directors for approval.  The information materials for grant submission and the application are available on the website.

 

The 2016 grants were awarded to the following investigators:

Sanford Research  -- Dr. Haotian Zhao                                                                                                                                                   Proposal titled: Molecular and Cellular Mechanisms of Choroid Plexus Tumors. 

Background. Choroid plexus (CP) tumors are rare brain tumors that are predominantly found in childhood and comprise 10-20% of all brain tumors in infants. CP papilloma (CPP) is benign, whereas CP carcinoma (CPC) is malignant. Despite excellent prognosis after surgical removal, incompletely resected CP tumors, recurrence or metastasis, as well as CPCs, can result in high morbidity and mortality rates. Multiple factors such as TP53 mutations, abnormal Notch signaling, and recurrent genomic changes, have been implicated in CP tumor; however, the cell of origin and molecular mechanisms of CP tumors remain incompletely understood. Our long-term objective is to understand the biology of CP tumors and identify targeted therapies for CP tumors that can be developed for use in humans.

Seattle Children’s Hospital- Dr. Courtney Crane                                                                                                                                   Proposal titled: Development of a novel cellular immunotherapy for children with brain tumors. 

Therapies for children with brain tumors are highly invasive, non-specific, and often cause devastating side effects. Clinical trials using lentivirally modified T cells indicate that activation of the immune system is sufficient to safely eliminate cancer in patients, without chemotherapy and radiation. For example, a single dose of T cells engineered to express chimeric antigen receptors (CARs) that specifically recognize and kill tumor cells induces remission in children with relapsed leukemia. Unfortunately, similar strategies for patients with solid tumors fail. CAR T cells eliminate tumors that overexpress tumor antigens in xenograft mouse models, which lack many cellular and soluble components of an intact tumor microenvironment. When evaluated in patients, however, these same CAR T cells fail to eliminate tumors, suggesting that a suppressive tumor microenvironment is a significant obstacle to successful immunotherapy. We hypothesize that in patients with brain tumors, local immunosuppression mediated by tumor cells and the cells that they recruit, such as regulatory T cells and myeloid cells, inhibit activation of cytotoxic immune effector cells and allow tumor growth. This proposal will create a novel immune therapy using genetically engineered monocytes (GEMs) that will support Natural Killer (NK) cell functions in the tumor microenvironment

Regents of the University of Michigan -- Dr. Sriram Venneti                                                                                                               Proposal titled: Targeting glutamine metabolism in histone K27M mutant gliomas. 

One of the fundamental mechanisms that drive cancer is reprogramming of cellular metabolism enabling tumors to take up and metabolize nutrients in vast quantities. Glutamine (Gln) is the most abundant plasma amino acid and is metabolized to _-ketoglutarate (_-KG) by tumors to fuel the tricarboxylic acid (TCA) cycle. Moreover, Gln-derived _-KG is a critical cofactor for the Jumonji C family of histone lysine demethylases that hypomethylates histone residues including H3K27. Therefore Gln is a key nutrient that regulates survival and proliferation of cancer cells by rewiring both cellular metabolism and epigenetics. Gliomas that bear histone H3K27M mutations including pontine gliomas (~80% cases) are lethal pediatric tumors with no effective treatments. Due to H3K27M mutations, there is global reduction in H3K27 trimethylation. However, how these gliomas rewire metabolism, specifically Gln metabolism to regulate the TCA cycle and H3K27 hypo-trimethylation represent a significant gap in our knowledge. Preliminary studies indicate that glioma cells that bear H3K27M take up large amounts of Gln and are addicted to Gln for their survival and proliferation.

Further, we have developed an FDA-approved, non-invasive, positron emission tomography (PET) imaging method to evaluate Gln uptake in vivo in adult glioma patients (Venneti et. al. Science Translational Medicine, 2015) and aim to translate this to pediatric glioma patients. Expected impact and significance: We expect that understanding Gln metabolism in H3K27M gliomas

Weill Medical College of Cornell University - Dr. Richard Ting                                                                                                           Proposal titled: Image guided design and delivery of DIPG drugs and nanoparticles.

The current measure for effective drug delivery to a brain tumor requires us to wait for a clinical response (disease-free interval, survival, or a reduction in tumor volume). A failed delivery can miss a tumor or aid in tumor’s chemo-resistance. In this scenario, the current metrics are unacceptable, as they would only register after a tumor has progressed significantly. A reliable and noninvasive, image-based assessment of drug delivery is needed to evaluate dosing and route-of-delivery, when early intervention is possible. Phase 0 trials are built on this premise of monitoring tumor response as a correlate of effective drug delivery on an agent-by agent basis. The solution is a theranostic agent, a noninvasive marker of delivery that simultaneously holds therapeutic potential. We propose new technology for quantitatively imaging drug delivery to DIPG. The quantitation of drug delivery could explain why we can be eradicate DIPG in ex vivo studies, but cannot use the same agents, in vivo, to cure patients. Recent preliminary data generated from collaborative efforts support this strategy. In collaboration with the Souweidane lab, we have developed an imaging technology that allows us to monitor Sprycel (Dasatinib)

 

The 2015 grants were awarded to the following investigators:

Dr. Pratiti Bandopadhayay & Dr. Susan Chi
Project Title: Feasibility of treatment with surgery and chemotherapy only for children with Wnt-positive Medulloblastoma
Dana Farber Cancer Institute

Medulloblastoma is the most common malignant brain tumor of childhood. The standard of care is maximal surgical resection followed by radiation and chemotherapy.  However, radiation therapy has significant long-term side effects including neurocognitive deficits, increased risk of second cancers, the formation of abnormal blood vessels, and the need for hormone replacement therapy and growth deficits.

Recently, with increasing sophistication of methods to profile the genomes of tumors, it has been recognized that there are four distinct subgroups of medulloblastoma.  One of these subgroups is characterized by up-regulation of a cancer pathway called the Wnt pathway (Wnt-positive medulloblastoma).  Children with Wnt-positive medulloblastoma have been shown to have excellent survival with rates of close to 100%. This has raised the question of whether therapy can be safely reduced in these children to minimize long term side effects.

This pilot study will examine the safety of omitting radiation therapy in children with Wnt-positive medulloblastoma.  Children who are identified to have Wnt-positive medulloblastnmas will be treated with maximal surgical resection followed by chemotherapy but no radiation therapy.  The outcomes of children treated without radiation therapy will be carefully monitored and compared.  If this study shows that children with Wnt-positive medulloblastoma can be safely treated without radiation therapy it may change the way that these children are treated in future and could spare children the long-term side effects associated with radiation therapy.

 

 

 

 

 

  Dr. Margarita Gutova
Project Title: Human Neural Stem Cell-Mediated Drug Delivery for Targeted Treatment of Medullloblastoma
City of Hope National Medical Center

Medulloblastoma is the most common malignant brain tumor of childhood. Current therapies are often severely damaging to brain development and skeletal growth. Therefore, new treatments are critically needed to improve the survival and quality of life of children with medulloblastoma. Major obstacles to successful treatment of pediatric brain tumors include the blood-brain-barrier (BBB), which prevents many anti-cancer agents from entering the central nervous system, and limitations on the amount of chemotherapy that can be given in a dose due to toxicity to normal tissues.

Neural stem cells (NSCs) offer a novel way to overcome these obstacles because they can cross the BBB and migrate to and selectively target tumor cells throughout the brain. NSCs can be genetically modified to act as delivery vehicles for targeted cancer therapy, thereby increasing the tumor-localized concentrations of a drug while minimizing toxicity to normal tissues and the side effects of therapy. The goal of this study is to determine the preclinical effectiveness of an NSC-mediated therapy against two subtypes of medulloblastoma, including Group 3 medulloblastoma, the most aggressive subtype of the disease. We will also investigate a novel, non-invasive route of NSC delivery to the central nervous system - intranasal injection.  This study has tremendous potential significance because NSC-hased delivery of chemotherapy could improve survival and minimize the serious brain damage caused by current radiation and chemotherapy regimens, thus preserving intellectual function and improving the quality of survivorship of young children with brain tumors.

 

 

 

The 2014 grants were awarded to the following investigators:

Jiangbing Zhou MD, PhD

Project Title: Precise delivery of gene therapy

Yale University

Brainstem gliomas, accounting for 10-20% of childhood brain tumors, are the main cause of death in this young group. The most common type of brainstem glioma is defined as diffuse intrinsic pontine glioma (DIPG). Despite extensive efforts over the past few decades, the overall prognosis for DIPG remains dismal – nearly 90% of children with this disease die within 18 months of diagnosis and the median survival have been about 1 year. The failure of current treatment can be attributed to two major reasons. First, current technologies don’t allow for efficient delivery of therapeutics precisely to DIPG tumors in the brain. Secondly, the existing regimen has limited efficacy on this genetically distinct disease. We hypothesize that improved treatment of DIPG can be achieved by adequately addressing these limitations through precise delivery of gene therapy designed for targeting major aberrant genes identified in this tumor. Specifically in this one-year project, we propose to develop a nanotechnology-based platform for image-guided delivery of gene therapy precisely to DIPG tumors in the brain. The success of this project, which we expect based on our existing progress, will result in a new approach for improved treatment of DIPG that can be readily translated into clinical applications to improve the quality of life and the survival rates of children and their families dealing with this lethal disease.

 

Hector Peinado Selgas MD, PhD

Project Title: Use of circulating exosomes as surrogate markers of signaling activation and response to therapy in pediatric brain tumors.

Weill Cornell Medical Center

 

Pediatric gliomas and medulloblastomas account for more brain tumors in children than any other. While surgery, chemotherapy and radiation remains the mainstay of upfront treatment, recent advances in molecular interrogation of brain tumors have demonstrated a small number of recurring genetic mutations in these tumors that might be exploited therapeutically. Diagnosis of brain tumors is generally based on imaging features and, when the tumor is biopsied or resected, histopathologic interpretation. Therefore, invasive techniques are normally needed to validate the mutational status and/or determine the activation of specific pathways. Activation of different oncogenic pathways has been found to be crucial for pediatric brain tumor progression. However, there are limited clinical trials for specific inhibitors. Novel therapeutic approaches are urgently needed to improve prognosis and treatment of these patients. We have recently found that small vesicles secreted from the tumor (called exosomes) are shed from cancers and are readily isolated from the peripheral circulation. We have found that exosomes shed from tumor cells contain many molecules representative of the primary tumor (i.e. activated oncoproteins and mutated DNA). Our results demonstrate that exosomal DNA may be used as a surrogate for tumor tissue to determine mutation status in cancer patients. We propose a novel concept in pediatric cancer: that tumor circulating exosomes in the plasma can be used to monitor oncogene activation and tumor DNA mutations.  Our studies will contribute to improve prognosis of pediatric brain cancer progression developing new approaches to monitor response to therapy.

 

 

Michelle Monje MD, PhD

Project Title: Neuronal: glioma interactions in the pediatric glioma microenvironment as a novel therapeutic target

Stanford University

 

Cancer cells grow in the environment of the tissue they are invading, and often take advantage of growth signals present in the normal tissue. This is especially true for cancers of childhood, when normal tissue is naturally in a state of growth and development. High-grade gliomas of childhood, the leading cause of brain tumor death in children, arise from glial precursor cells in the context of the developing brain. Our previous studies of normal childhood brain development indicate that neurons, the electrically active cells in the brain, influence the growth of glial cells such that active neural circuits receive more glial support. We hypothesize that pediatric gliomas may be similarly influenced by the growth-promoting effects of active neurons. Using a revolutionary new technique called “optogenetics”, we can control the firing rate of neurons using pulses of light. We find that indeed there is an important interaction between active neurons and pediatric glioma cells. Our preliminary studies indicate that active neurons secrete a molecular factor (or factors) that induces a significant increase in glioma cancer cell growth. In the present proposal, we seek to identify the molecular factor (or factors) responsible for this cancer growth-promoting effect. We hope that this work will result in novel therapeutic strategies for high-grade gliomas of childhood.

 

Rintaro Hashizume, MD, PhD

 

Targeting the Histone H3.3-K27M Mutation for the Treatment of Diffuse Intrinsic Pontine Gliomas

University of California, San Francisco

 

Diffuse intrinsic pontine gliomas (DIPGs) in children continue to carry a very poor prognosis despite the use of intensive multi-modality treatment. No significant advances in the survival of DIPG patients have been made over the last few decades, and new therapeutic approaches are desperately needed. The lack of human DIPG tissue samples and a faithful experimental model system, combined with a limited understanding of the development of childhood brainstem tumors, have hindered the study of this devastating disease, and prevented the identification of effective therapeutic strategies. Recent genetic screenings identified a specific mutation of histone gene H3F3A in DIPGs, thereby suggesting a role of this mutation in DIPG development. We have recently established tumorigenic DIPG cells from biopsies of pediatric DIPGs, and these have been determined as having the H3F3A mutation in question. These DIPG cells produce tumors in athymic mice, and provide an excellent resource for studying the biological abnormalities of these tumors, as well as for testing experimental therapies for treating DIPGs. The overall goal of this project is to investigate molecular consequences of the H3F3A mutation, and to evaluate a specific therapeutic for treating these tumors. This project has a high likelihood of influencing DIPG treatment, and for achieving improved outcomes for DIPG patients.

 

J. Anthony Graves MD, PhD

Therapeutically Targeting OPA1 in Medulloblastoma

University of Pittsburg

Medulloblastoma, the most common malignant pediatric brain tumor, results in significant morbidity and mortality. Specifically, there is one subtype of medulloblastoma that is responsible for the vast majority of tumor-associated morbidity, which is characterized by amplification of the c-Myc oncogene. Among the changes that result from c-Myc overexpression is an increase in mitochondrial fusion. Decreasing the expression of Opa1, a protein essential for mitochondrial fusion, has been shown to kill a variety of cells that overexpress c-Myc. It is proposed to exploit this finding for possible novel treatments of medulloblastoma with high levels of c-Myc.

 

 

 

Ranjit Binja MD, PhD

Creation of Isogenic Pediatric Glioma cell lines for High-throughput drug screening campaigns

Yale University

Pediatric high-grade gliomas (HGGs) are clinically devastating tumors, with associated 5-year overall survival rates of less than 20%. There have been little improvements in survival for this disease over the last 30 years. Most novel therapies for pediatric HGGs are tested in children based on extrapolation from adult

HGG studies. However, it is now understood that significant genetic differences exist between gliomas arising in children and adults. In parallel, there is a lack of suitable pediatric glioma cell lines, which can be used for translational research studies. We hypothesize that better cell line models will facilitate drug screening efforts to identify pediatric glioma-specific therapies. In this project, we propose to create a panel of novel glioma cell

lines which harbor mutations in key genes specific to pediatric HGGs. We will characterize these cell lines in a panel of genomics-based studies, and we will provide them to the broader pediatric glioma research community for future research efforts. These cell lines do not currently exist, and they are likely to become indispensable tools for future drug screening efforts.

 


The 2013 grants were awarded to the following investigators:

Dana Farber Cancer Institute
Dr. Pratiti Bandopadhayay
Dr. Susan Chi
Feasibility of treatment with surgery and chemotherapy only for children with Wnt-positive Medulloblastoma


Medulloblastoma is the most common malignant brain tumor of childhood. The standard of care is maximal surgical resection followed by radiation and chemotherapy.  However, radiation therapy has significant long-term side effects including neurocognitive deficits, increased risk of second cancers, the formation of abnormal blood vessels, and the need for hormone replacement therapy and growth deficits.

Recently, with increasing sophistication of methods to profile the genomes of tumors, it has been recognized that there are four distinct subgroups of medulloblastoma.  One of these subgroups is characterized by up-regulation of a cancer pathway called the Wnt pathway (Wnt-positive medulloblastoma).  Children with Wnt-positive medulloblastoma have been shown to have excellent survival with rates of close to 100%. This has raised the question of whether therapy can be safely reduced in these children to minimize long term side effects.

This pilot study will examine the safety of omitting radiation therapy in children with Wnt-positive medulloblastoma.  Children who are identified to have Wnt-positive medulloblastnmas will be treated with maximal surgical resection followed by chemotherapy but no radiation therapy.  The outcomes of children treated without radiation therapy will be carefully monitored and compared.  If this study shows that children with Wnt-positive medulloblastoma can be safely treated without radiation therapy it may change the way that these children are treated in future and could spare children the long-term side effects associated with radiation therapy.

City of Hope National Medical Center  
Dr. Margarita Gutova
Human Neural Stem Cell-Mediated Drug Delivery for Targeted Treatment of Medullloblastoma


Medulloblastoma is the most common malignant brain tumor of childhood. Current therapies are often severely damaging to brain development and skeletal growth. Therefore, new treatments are critically needed to improve the survival and quality of life of children with medulloblastoma. Major obstacles to successful treatment of pediatric brain tumors include the blood-brain-barrier (BBB), which prevents many anti-cancer agents from entering the central nervous system, and limitations on the amount of chemotherapy that can be given in a dose due to toxicity to normal tissues. 

Neural stem cells (NSCs) offer a novel way to overcome these obstacles because they can cross the BBB and migrate to and selectively target tumor cells throughout the brain. NSCs can be genetically modified to act as delivery vehicles for targeted cancer therapy, thereby increasing the tumor-localized concentrations of a drug while minimizing toxicity to normal tissues and the side effects of therapy. The goal of this study is to determine the preclinical effectiveness of an NSC-mediated therapy against two subtypes of medulloblastoma, including Group 3 medulloblastoma, the most aggressive subtype of the disease. We will also investigate a novel, non-invasive route of NSC delivery to the central nervous system - intranasal injection.  This study has tremendous potential significance because NSC-hased delivery of chemotherapy could improve survival and minimize the serious brain damage caused by current radiation and chemotherapy regimens, thus preserving intellectual function and improving the quality of survivorship of young children with brain tumors.


The 2012 grants were awarded to the following investigators:

1) Richard C. E. Anderson, M.D. Assistant Professor of Pediatric Neurosurgery, Columbia University College of Physicians and Surgeons. The proposal is titled: : Tumor Associated Monocytes/Microglia are a Requisite Target for Immunotherapy in Malignant Gliomas.

The outcome for children with malignant gliomas has not significantly improved over the last 25 years despite technical advances in neurosurgery, radiotherapy, and the development of novel chemotherapeutic agents. Due to limitations of the current standard of card, studies examining the efficacy of immune mediated destruction of malignant gliomas have been pursued for many years. While the majority of immunotherapy research thus far has focused on T cell lymphocytes, we have observed that tumor-associated monocytes/microglia (TAMs), which are immunostimulatory cells with the potential for tumoricidal activity, in fact represent the predominant infiltrating immune cell population in gliomas. We hypothesize that malignant gliomas actively inhibit TAM function and prevent the immune system from mounting an effective immune response against these tumors. We have recently demonstrated using complementary approaches that malignant glioma tumor cells suppress the immunostimulatory function of TAMs. Using a microarray approach we then identified a short list of genes that are strong candidates responsible for the immunosuppressive phenotype in TAMs. We then blocked expression of these candidate genes and were able to identify one gene that when blocked restored significant TAM function. The goal of the present study is to determine if blockage of our identified gene and restoration of TAM function will prolong survival in our murine glioma model. Our collective data, together with the proposed studies, will allow us to identify pharmacologic compounds that could be used in a subsequent clinical phase I study designed to restore TAM function in children and adults with malignant gliomas.

2) Jeffrey P. Greenfield M.D., Ph.D, Weill Medical College of Cornell University. The proposal is titled: Exosome Recruitment of Bone Marrow-Derived Cells Mediates Glioma Transformation.

Many brain tumors in the pediatric and young adult populations initially begin as lower grade tumors with a comparatively better prognosis initially. However, these tumors can transform into malignant high-grade gliomas characterized by profound neovascularization. In our laboratory we investigate the mechanism through which these new blood vessels are stimulated to begin growing and the environment, which supports their growth. We have begun to explore a novel particle called an exosome which is derived from pediatric brain tumor samples - essentially a small piece of the tumor’s genetic material broken off in a small capsule. We are exploring the fundamental mechanisms through which these particles exert malignant phenotypes through the recruitment of blood vessel precursor cells from bone marrow into the tumors. Our hypothesis is that a series of events beginning with these exosome being released by the tumors may initiate the transformation of low-grade tumors into higher-grade gliomas such as glioblastoma multiform through recruitment of cells that live in the bone-marrow. We have shown that patients with higher grade tumors have more of these exosomes, and by discovering their contents and the genetic messages they are relaying we hope to be able to interrupt the recruitment of the blood vessels these tumors need to grow and invade.

3) Sabine Mueller, M.D., Ph.D. Assistant Professor, The Regents of the University of California, San Francisco. The proposal is titled: Targeting Key Cell Cycle Regulatory Kinases for the Treatment of Pediatric Malignant Gliomas.

Pediatric high-grade gliomas continue to have a discouraging prognosis and new treatment approaches are urgently needed. Despite decades of efforts to improve surgery, radiation, and chemotherapy, most children succumb to their disease. A dearth of information regarding molecular events underlying pediatric glioma development and resistance to treatment has hampered efforts to rationally incorporate biologically targeted agents into treatment regimens. Our preliminary studies have shown that the key cell cycle kinases Chk1 and WEE1 are up-regulated in malignant pediatric gliomas and that inhibition of WEE1 with the small molecule inhibitor MK-1775 in combination with radiation improves survival in highly relevant models of pediatric gliomas. This application focuses on expanding on these exciting findings using the specific Chk1 inhibitor AZD7762 for the treatment of malignant gliomas. Furthermore, we aim to assess potential mechanism of resistance to such treatment. We chose inhibitors that have already entered clinical trials for adults and/or children in order to facilitate and hasten transition into the clinic. Results of this proposal will deliver the preclinical rational for clinical trials of these agents for children with malignant gliomas.

4) Eric Hutton Raabe, M.D., Ph. D, Johns Hopkins University, School of Medicine. The proposal is titled: Targeting Diffuse Intrinsic Pontine Glioma by Blocking the Notch Pathway.

Diffuse Intrinsic Pontine Glioma (DIPG) is a universally fatal pediatric brain tumor. It comprises nearly 15 percent of all pediatric brain tumors. Because of the characteristic MRI appearance and inoperative nature of the tumor, there has traditionally been little tissue available for research. That is now changing due to rapid autopsy programs. Our laboratory now has several DIPG cell lines derived from rapid autopsies, which we will use to test new therapies. One of the more promising molecular signaling systems that we can target is the Notch pathway. Notch regulates cellular growth and maturation as well as resistance to radiation and chemotherapy. This pathway is active in DIPG in general and in our cell lines specifically. Notch is targeted by drugs that have good penetration into the brain, making them good candidates for therapeutics for brain tumors. We will focus on MRK-003, a Notch inhibitor that our lab has shown can decrease the growth of other aggressive brain tumors. Our hypothesis is that MRK-003 will block Notch signaling in DIPG cells, and that blocking Notch will lead to decreased growth of DIPG cancer cells in cell culture and when the tumor cells are transplanted into the brains of mice. We also believe that blocking Notch will enhance the effect of radiation and chemotherapy, which are the traditional treatments for DIPG. Taken together, the experiments we propose in this translational grant application will set the stage for testing of novel treatments for children with this incurable, invasive brain tumor.

 

 


 

 

 The 2011 grants were awarded to the following investigators:

1) Reema Habiby, MD, Children’s Memorial Hospital, Chicago. The proposal is titled: Epigenetic Mechanisms of Regulation of Progression in Craniopharyngiomas: Understanding Their Biology and Uncovering New Therapeutic Targets.

Craniopharyngiomas are brain tumors that arise from remnants of Rathke’s pouch, a structure in the developing embryo arising from the roof of the mouth that becomes part of the anterior pituitary gland (master gland) prior to birth. These tumors, although benign, frequently invade surrounding brain structures leading to hormone dysfunctions and visual problems. Compression of the hypothalamus, the part of the brain just above the pituitary, can lead to severe weight gain, profound fatigue, difficulty regulating body temperature, and cognitive changes. The current treatment for craniopharyngiomas is surgery, with or without radiation therapy. Although surgery can sometimes result in a cure, it can also lead to permanent damage due to the disruption of the Rathke’s pouch, we believe that there is abnormal development of Rathke’s pouch into the pituitary gland that leads to these tumors. While there is research into other brain tumors examining the cause of the change from a normal cell line to an abnormal cell line, little information of this nature exists on craniopharyngiomas. To obtain this information, we will examine the tissue of patients with craniopharyngiomas to determine the expression of small RNAs, called microRNAs, needed for proper development of the pituitary gland. Evaluating the microRNAs in these patients will help to provide insight into the cause of craniopharyngiomas with the hope of targeting new treatment approaches to minimize the poor long-term outcomes of craniopharyngiomas associated with the current surgical procedures and radiation therapies.

2) Zhiping Zhou, MD, PhD, Weill Medical College of Cornell University. The proposal is titled: Targeting Signal Transduction Pathways for the Treatment ofPediatric Pontine Glioma.

Brain tumors are one of the most common cancers in children and are the leading cause of cancer death of childhood. Diffuse intrinsic pontine glioma (DIPG), the deadliest of childhood brain cancers, is located in the brain stem, which is the center that controls basic life functions such as breathing, heart beat, blood pressure, swallowing and etc. DIPG has no known cure. Nearly no children with this cancer will survive beyond 1-2 years following diagnosis with current standard therapy. Recently two key signals driving tumor growth in this disease have been identified. Experimental therapies targeting these two overactive signals will be tested in this proposed study. To overcome the obstacle that drugs do not get into the tumor, we will deliver the drugs directly into the tumor using a technique called convection enhanced delivery (CED). By using combinations of drugs, we expect to slow or even stop growth of the tumor. Additional therapeutic targets will also be screened for using a modern technology called microarray analysis. We expect new therapeutic targets will be found. These efforts will eventually improve the clinical outcomes of patients with DIPG.

3) Robert A. Johnson, Ph.D, WResearch Institute at Nationwide Children’s Hospital. The proposal is titled: Determining the impact of EphB2 over expression on radial glia differentation and transformation ependymoma.

Ependymoma is the third most common pediatric brain tumor and can develop throughout the ventricular lining of the central nervous system. Surgery and irradiation are the preferred forms of treatment; however, more than half of the cases occur in the brains of children under 5 years of age, making irradiation extremely hazardous. Adding to the problem is the fact that ependymomas are largely chemo resistant further limiting treatment options and contributing to the low cure rate of 60%. The lack of model systems in which to study disease development has greatly hindered the identification of new drug targets. Fortunately, a mouse model for ependymoma was recently developed by over expressing the tyrosine kinase receptor EphB2 in the mouse Ink4a/ARF(-/-) embryonic neural stem cells (eNSCs) called radial glia (RG). This achievement opens the door for the first studies investigating the abnormal changes leading to ependymoma formation. Analysis of the gene expression profiles of both the human and mouse tumors showed an enrichment of genes involved in neuronal differentiation and maintenance suggesting that these pathways may play a part in disease development. The EphB2 protein consists of a several functional domains known to initiate a number of signaling pathways affecting several neuronal processes. We are interested in determining the role of key EphB2 functional domains on RG cell differentiation and determine their impact on ependymoma formation. In addition, we hope to identify the signaling pathways involved in this process in hopes of identifying novel avenues for chemotherapeutic treatment. 

 

 


 

 

The 2010 grants were awarded to the following investigators:

1) Rachid Drissi, PhD, Assistant Professor at the Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio. . The proposal is titled: Telomerase: A Therapeutic Target in Pediatric Brain Tumors.

The outcome for children with may brain tumors remains poor. Current standard therapy for children with high-grade glioma that includes radiotherapy has devastating side effects on the child’s life. The long-term goal of this pilot study is to improve the efficacy of radiation while minimizing its side effects. This project is design is to use radiation concurrently with a compound that sensitizes cancer cells to radiation therapy. This combination therapy is expected to be more effective at lower radiation doses and therefore will minimize the side effects.

2) Dr. Jason Fangusaro, MD, assistant professor at Children's Memorial Hosiptal in Chicago, IL, and Vidya Gopalakrishnan, PhD, assistant professor at MD Anderson Cancer Center in Houston, TX. Their proposal is titled: RE1 Silencing Transcription (REST) Factor as a Prognostic Factor and Therapeutic Target for Medulloblastoma.

Currently, the prognosis for Medulloblastoma in children is based on non-specific factors like age of the child and spread of the tumor. This study aims to find out if RE1 Silencing Transcription Factor (REST) could be used as a prognostic factor. REST helps block the generation of neurons from stem cells until the appropriate time in the cell life and recently been found in human Medulloblastoma samples. This study will examine the relationship between REST and Medulloblastoma and will look for opportunities to target REST expression.

3) Dr. Christopher Pierson, MD, PhD, assistant professor at Nationwide Children’s Hospital in Columbus, OH. The proposal is titled: Id Proteins in MedulloblastomaMedulloblastoma is the most common malignant childhood brain tumor.

Id proteins are abundant in many types of cancers but minimal or absent in normal cells. These proteins are important in cell proliferation, survival and invasion of malignant cells and are therefore an appealing anti-tumor target. This project looks to evaluate the role of Id proteins in Medulloblastoma and the feasibility of targeting them as a new treatment approach.

4) Angela Sievert, MD, MPH, instructor at the Children’s Hospital of Philadelphia in Philadelphia, PA. The proposal is titled: Targeting Activating BRAF Mutations in Pediatric Brain Tumors

Gliomas are the most common type of brain tumor in children and the long term prognosis can be favorable if the tumor can be completely removed. Treatment options are limited for the many children with unresectable or recurrent tumors. If effective, targeted therapies could be directed against specific biochemical or cellular abnormalities of these tumors. Mutant BRAF activation is a hallmark of pediatric gliomas and therefore a possible target. This study aims to test a panel of BRAF inhibitors in cell lines and mouse models to identify which are most promising therapies for pediatric gliomas.

 


 

One of the 2009-2010 grants were awarded to the following investigators:

1)      Weiling Zhao, Phd Assistant Professor from Wake Forest University Health Sciences in Winston-Salem, NC.  The proposal istitled:  Improving Quality of Life and Targeting Tumor Cells in Pediatric Brain Cancer Patients Using the PPARa Agonist, Fenofibrate. 

Current radiation and chemotherapy treatments have increased the 5-year survival rate to ~80% for children with brain tumors. These children are at a high risk of developing learning and memory deficits, psychological and behavioral problems, and secondary malignancies. At this time, more than 250,000 children in the US are already at risk of developing these conditions and/or are presently experiencing mild to severe problems with school performance, the ability to hold a job, and interactions in social settings. There are no long-term successful treatments for children with radiation-induced brain injury. Data from our lab suggest that fenofibrate not only inhibits both whole brain radiation-induced inflammation and the decrease in neurogenesis in adult rodents, but it also can kill brain tumor cells in tissue culture. It is well known that many treatments that work in adults do not work in children or are much more dangerous to children. However, until now, there has been no good animal model for studying treatments for pediatric radiation-induced brain injury. The successful completion of the proposed specific aims in this grant offers not only the promise of finding a treatment to overcome the late effects that occur in children surviving brain cancer, but it will also provide the data to submit a competitive NIH grant proposal to continue the search for treatments that will improve the quality of life for the survivors of childhood brain cancer.

 


 

The  2007-08 grants were awarded to the following investigators:

1)      Drs. Oren Becher and Rosandra Kaplan from MemorialSloan Kettering Cancer Center in New York City.  Their proposal istitled: Stromal Contribution of Bone Marrow Progenitors inMedulloblastoma

Meduloblastomas are brain tumors that arise in the cerebellum ofchildren.  Using animal models, this study examines whethermedulloblastomas contain cells that originate from the bone marrow. Recently, it has been observed that in adults, bone marrow derivedcells contribute to the formation of tumor blood vessels and assisttumor cells to invade normal tissue.  These researchers hypothesizethat these bone marrow derived cells act the same way in children’sbrain tumors.  Medulloblastoma cancer stem cells reside near bloodvessels and are more resistant to treatment with radiation andcisplatin.   Cells derived from the bone marrow may also be moreresistant to such treatment and may play a role in supporting thecancer stem cells.  In this study the researchers will use drugs thatinhibit bone marrow derived cells of medulloblastoma-bearing mice toassess if medulloblastoma tumor growth will be affected.  They will usethese inhibitors to determine if they increase the effectiveness ofradiation and chemotherapy.  They will also study the number of bonemarrow derived cells in the blood and cerebrospinal fluid of childrenwith brain tumors to determine if the number of these cells correlateswith the stage or tumor recurrence.  They hypothesize that drugs thatcan block bone marrow derived cells are potential novel treatments forchildren with brain tumors. 

2)      Dr. Mark Kieran from Dana-Farber CancerInstitute/Harvard University in Boston.  His proposal is titled:  PhaseI Study of AdV-tk+ Prodrug Therapy in Combination with RadiationTherapy for Pediatric Brain Tumors

Childhood brain tumors called gliomas – those that arise in the glialcells – typically have a poor outcome.  Patients suffering from thisdisease usually survive for only a short number of months, soinnovative approaches to treatment are critical.  .  This study is aPhase I clinical trial in which pediatric patients’ gliomas will beremoved surgically, and a gene therapy vector, AdV-tk, will be injecteddirectly into the tumor site.  In the days that follow, patients willreceive prodrug and standard radiotherapy; standard chemotherapy may beused as well.  This approach will allow simultaneous targeting of thetumor with multiple methods.  This multiple method therapy has beentested using animal models and has been successfully used in adultswith brain tumors and other cancers.  This combination therapy showsgreat promise as an improved form of treatment for children with braintumors.

3)       Dr. Joseph Lasky from UCLA in Los Angeles.  His  proposal is titled: Immunotherapeutic Targeting of Stem Cells in Pediatric Brain Tumors

Although surgery, chemotherapy, and radiation therapy work in somecases of childhood gliomas and medulloblastomas, the devastating sideeffects of these therapies and relative lack of efficacy necessitatethe development of novel, targeted therapies for the developing brain. In this study, the research looks to harness the power of a person’sown immune system to fight these tumors.  The researchers will attemptto identify immunogenic proteins expressed by the brain tumor stem cellpopulation.  The genes, Bmi-1, SOX2, MELK, and FoxM1 have been shown toplay critical roles in cancer growth.  T-cells which are capable ofproliferating and activating in response to these proteins will then betested against cell lines generated from pediatric tumor samples and inanimal models.  The results will be used to develop individualizedvaccines for pediatric patients with brain tumors.

 




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