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.