Pediatric brain tumors are the second most common form of cancer and the leading cause of cancer-related morbidity and mortality in pediatrics. Until recently, the majority of research in pediatric brain tumors was focused on the highly aggressive embryonal tumors, such as medulloblastoma, and there have been recent dramatic advances in the understanding of this subset of tumors.
However, more than half of childhood primary central nervous system tumors are gliomas and, unlike the situation in adulthood, low-grade gliomas constitute most pediatric gliomas. Pediatric low-grade gliomas arise throughout the nervous system and, despite their often indolent nature — dependent on their location in the nervous system — they may not be amenable to safe, extensive resections and can result in significant morbidity and, at times, mortality.
Radiation has been a conventional second step in therapy when surgery is not deemed feasible. In many children, this can result in excellent long-term control, but it also may result in long-term sequelae. These sequelae include acute deterioration due to radiation-induced necrosis and swelling, but radiation-associated intellectual deteriorations over time, hormonal deficiencies, cerebral vascular injury and secondary brain tumors are more frequent.
Because of these complications, alternative means have been sought to treat aggressive, nonsurgically resectable low-grade gliomas. During the past 2 decades, chemotherapy has been found to be surprisingly effective, despite the apparent slow growth pattern of these tumors. Chemotherapy was initially used to primarily delay the need for radiation therapy and, in up to one-third of patients, it may obviate the need for radiotherapy.
Despite the benefits of chemotherapy, such treatments are often only of transient benefit, and there have been recent concerns raised that despite radiographic stability during and after treatment, patients will continue to lose neurologic function, especially those patients with tumors in the visual pathway who may lose vision over time despite apparent successful treatment. For these reasons, alternative treatment options are being sought.
Currently, there is tremendous interest in utilizing other biologic approaches for pediatric low-grade gliomas. Probably more than three-fourths of pediatric low-grade gliomas are pilocytic astrocytomas. The vast majority, if not all, of pilocytic astrocytomas have been shown to have abnormalities in the RAS-MAPK signaling pathway. Abnormalities in BRAF (a component of the pathway), either activating fusion protein abnormalities or point mutations, have been shown to be present in most cases, and these abnormalities are molecular targets.
Studies are underway to evaluate drugs that inhibit the effects of BRAF-point mutations and other studies attempting to block RAS-MAPK kinase signaling with the use of MEK inhibitors (MEK being a component of the signaling pathway one step after BRAF). Other studies are attempting to turn off aberrant cellular signaling of pediatric low-grade gliomas further downstream by interfering with mTOR.
These exciting new approaches will need to be carefully evaluated, not only regarding efficacy in tumor control but also their ability to improve neurologic and/or visual function without causing short- and long-term unacceptable sequelae.
However…there is reason to be tremendously optimistic about the future of treatment for pediatric low-grade gliomas and the ability of molecularly targeted therapies to change the way patients with recurrent disease — and, in time, those with newly diagnosed disease — will be treated in the near future. (Dr. Roger J Packer, MD, Children’s National Medical Center, Center for Neuroscience Research, Director, Brain Tumor Institute.
Over the course of the past 11 years, A Kids’ Brain Tumor Cure has raised over $16.5 million and has funded a dozen international conferences, 5 clinical trials and 4 dozen research projects.
Conferences and Symposiums
- May 2014: LGG Kids Get International Attention at 2014 ISPNO
- June 2012: PLGA Foundation Sponsors International Low Grade Glioma Symposium
- October 2010: The Low Grade Glioma Symposium at SIOP
- June 2009: Advancing basic and translational research in Low Grade Astrocytoma – A Trials Consensus and Research Planning Meeting
- February 2009: Low Grade Glioma – Meta Analysis Symposium
- June 2008: Low Grade Glioma Symposium at the International Society of Pediatric Neuro-Oncologists
- May 2006: First JPA Researcher Symposium
AKBTC Sponsored Research:
- May 2018: Critical Mechanisms of Gene Regulation in Medulloblastoma
- March 2017: SickKids of Toronto, Dr. Uri Tabori: – Novel universal classification of childhood low grade gliomas using clinico-pathological and molecular methods.
- June 2016: DNA Analysis of Paediatric Low-Grade Astrocytomas Identifies Tumour-Specific Signature in Pilocytic Astrycotomas
- June 2016: Johns Hopkins Medical Center – Dr. Eric Raabe, Dr. Charles Eberhart, Dr. Fausto Rodriguez: Using Human Neural Stem Cells to Create Genetically Accurate Models of PLGG, Developing PLGG Models Using Patient-Derived Tumor Tissue, Dual mTOR/NOTCH inhibition as a Therapeutic Strategy for PLGG
- November 2015: Long Term Clinical Implications of PLGG Molecular Subgroups
- September 2015: Genomic Analysis of Matched Primary and Progressive Recurrent PLGAs
- March 2015: Genomic Investigation of Medulloblastoma (3/2015)
- June 2014: Clinical Research Assistant for Tissue Harvesting Initiative
- January 2014: Johns Hopkins Lands Funding Based on Collaborative Project Model
- January 2014: Dana Farber Cancer Institute’s Pediatric Brain Cancer Research is Producing Results
- June 2013: DFCI Clinical Research Assistant – Tissue Harvesting
- January 2013: Evaluation of MYBL1 fusion oncogene in pediatric diffuse astrocytoma
- January 2013: Neural Stem Cells and Low Grade Glioma
- January 2013: Children’s Hospital of Philadelphia (CHOP) Joins the Fight Against PLGA
- January 2013: PLGA Research Program at Dana Farber
- July 2012: Genomic Investigation of Medulloblastoma (7/2012)
- March 2012: Development of Permanent Juvenile Pilocytic Astrocytoma Cell Lines for Preclinical Trails
- March 2012: Controlling Pilocytic Astrocytoma Growth: Effects of location, age and Telomerase
- March 2012: Identification of Key Genetic and Growth Control Pathway Changes in JPA that Represent Potential Molecular Targets for…
- March 2012: Molecular Pathology and Genetics of Low Grade Glioma, Focus on Diffuse Astrocytoma (WHO Grade II)
- August 2010: ChIP/Seq Core
- August 2010: RNAi Screening Core
- August 2010: Mouse Modeling Core for Invivo Drug Testing
- June 2010: Genetic Characterization Grade II LGA
- March 2009: PLGA: Dedicated Tumor Banking and Establishment of Cell Lines and Xenografts (PDF)
- November 2008: Analysis of BRAF in WHO Grade II Fibrillary Pediatric Astrocytomas [PDF]
- October 2008: Peptide Vaccine Based Immunotherapy for Pediatric Low-Grade Glioma
- October 2008: Identification of the Molecular Signature of Progressive JPA
- October 2008: Xenograft Mouse Models of Childhood Low-Grade Glioma
- October 2008: Targeting the Hedgehog Pathway in Pediatric Low-Grade Glioma
- May 2007: Identification of Key Genetic and Growth Control Pathway Changes in Fibrillary Astrocytoma that Represents Potential Molecular.
- May 2007: Controlling Pilocytic Astrocytoma Growth: Effects of location, age and Telomerase
- May 2007: Development of Permanent Juvenile Pilocytic Astrocytoma Cell Lines for Preclinical Trails
- May 2007: Molecular Prognostic Markers for Low-Grade Gliomas
- May 2007: The Biologic and Prognostic Role of Replicative and Oncogene Induced Senescence
- May 2007: Targeting Cancer Stem Cells in Pediatric Fibrillary Astroctyoma
- May 2007: Establishment of PLGA Research Program
- May 2006: Molecular JPA Study
- March 2006: Identification of Key Genetic and Growth Control Pathway Changes in JPA
- March 2006: Identification of Key Genetic and Growth Control Pathway Changes in JPA that Represent Potential Molecular Targets for Therapuetic Intervention
- June 2018: A Phase I Study of PLX8394 Plus Ritonavir in Children with Recurrent or Progressive BRAF Activated Gliomas
- May 2018: A Phase I/II and Target Validation Study of TAK-580 (MLN2480) for Children with Low-Grade Gliomas and Other RAS/RAF/MEK/ERK Pathway Activated Tumors
- January 2018: Phase 1 study of APX-005M CD40 agonist antibody in children and young adults with CNS tumors
- August 2016: Phase 1/II Study of MEK162 for Children with Ras/Raf Pathway Activated Tumors
- May 2016: Phase I Immunotherapy Study of Nivolumab mono therapy and in combination with ipillmumab
- January 2015: Phase III Study of Prospective Assessment of Vincristine and Vinblastine in Carboplatin-based Chemotherapy
- December 2013: Clinical Trial: Determinants of Response and Resistance in PLGG – Everolimus
- May 2011: NEW Sorafenib clinical trial OPEN for enrollment
- October 2008: A Phase II Study of RAD001 for Children with Chemotherapy Hemotherapy
With continued education and research funds, we can begin to imagine targeted therapies that arrest the development and potentially cure patients suffering from the most common forms of children’s brain tumors.
Please Donate to A Kids’ Brain Tumor Cure Foundation (aka PLGA Foundation) today. Your generosity can bring us one giant step closer to a 100% cure!