Laboratory of Dr. Javad Nazarian, Center for Genetic Medicine, Children’s National Health System
Primary CNS tumors are the most common pediatric solid cancer, and account for 23% of malignancy in children under 15 years of age, second only to leukemia. The incidence of newly diagnosed brain tumors in the pediatric population is 3.3 cases per 100,000 children, with 3000 children diagnosed annually. Brain tumors are also the leading cause of cancer death in children. Pediatric brain tumors differ from brain tumors in adults. In adults, supratentorial high grade glioma (WHO-Grade IV), also known as glioblastoma multiforme, is the most common primary brain tumor. In contrast, over 60% of pediatric brain tumors are infratentorial, occurring below the tentorium in the cerebellum or brainstem, and pediatric gliomas are more often low grade (WHO-Grade I-II). In addition, brainstem gliomas are exceedingly rare in adults, while 10-15% of pediatric brain tumors are localized to the brainstem. Over 50% of pediatric brainstem tumors are brainstem gliomas.
Pediatric Brainstem Gliomas (BSGs) and Diffuse Intrinsic Pontine Gliomas (DIPGs)
Brainstem Gliomas (BSGs) affect 200-300 children in the United States each year, and are the leading cause of brain tumor death in children. BSG’s are classified into four categories on the basis of anatomic location and radiographic appearance: diffuse, focal intrinsic, focal exophytic, and cervicomedullary. Of these, the most common form is Diffuse Intrinsic Pontine Glioma (DIPG), accounting for 80% of all brainstem gliomas.
Tumor cells of a developing DIPG gradually compress crucial nuclei and tracts within the pons. As the tumor enlarges, it causes symptoms due to impaired function of neurons arising in or running through the pons that carry information to and from the cerebellum, cerebral cortex, spinal cord, and cranial nerves. The most common symptoms are a triad of 1) cerebellar deficits such as impaired balance and coordination, 2) long tract impairment causing weakness or sensory loss of the extremities or trunk, and 3) paresis of cranial nerves VI and VII, which facilitate outward movement of the eye and face, respectively. Headaches, altered level of consciousness and other cranial nerve deficits due to obstruction of cerebral spinal fluid flow due to tumor impingement on the ventricular system of the brain, are also not uncommon. Once a clinician suspects a brainstem abnormality, the radiologic study of choice is Magnetic Resonance Imaging (MRI). DIPG has a peak incidence of 6-9 years and typically exhibits rapid clinical onset and progression with 90% mortality rate within 18 months of presentation.
Currently, there are no effective treatments for DIPG. Due to the anatomic location and infiltrative nature of DIPG, these tumors are not amenable to surgical resection. Diagnosis is based on characteristic appearance on MR Imaging, so diagnostic biopsy is rarely performed except in rare cases where diagnosis is uncertain. As a result, tumor tissue for pathologic evaluation and molecular study is rare, and little is known about the molecular biology of DIPG compared to other gliomas, making treatment more challenging. Conventional radiation therapy (RT) is typically used for palliation, providing a transient improvement in neurologic function and progression free survival benefit up to one year with minimal side effects. However, median onset of disease progression following RT is less than 6 months, with no improvement in overall survival. Prolonged survival up to 24 months has been observed in less than 10% of patients. Clinical trials to date have not led to advancement in the treatment paradigm of DIPG. Hyperfractionated RT provides no survival benefit compared to conventional or hypofractionated RT, with increased toxicity. Likewise, clinical trials of single and multi-agent regimens of conventional, myeloablative and radiation sensitizatizing chemotherapeutics have been conducted with no effect on outcome. Varied timing of administration with radiation has also shown no appreciable change in median survival or survival benefit.
New clinical trials are currently underway, investigating novel medications and therapeutic techniques in an effort to better treat patients with DIPG. A number of centers, including St. Jude’s Children’s Research Hospital and National Cancer Institute, are investigating new combinations and dosages of chemotherapeutic agents in conjunction with RT for patients with DIPG. National Institute of Neurological Disorders and Stroke, part of National Institutes of Health, is conducting a trial of an experimental drug, IL13-PE38QQR, for the treatment of DIPG and other high grade gliomas using a technique termed convection enhanced delivery (CED) which involves inserting a catheter into the brain and directly administrating the medication to the tumor itself.
The diffuse nature and location of DIPG precludes surgical removal, and biopsy is not routinely performed for diagnosis, so there is a paucity of fresh tumor tissue for researchers to study. Rare biopsy and post mortem specimens have revealed histological characteristics typical of high grade glioma (WHO-III or IV), including microvascular proliferation, cellular necrosis and the presence of mitotic figures. However further research has shown that pediatric high grade gliomas are biologically distinct from adult high grade gliomas.
Recent technological advances have made rapid profiling of tumor DNA and RNA arrays possible, revealing differences in gene expression that could help explain tumor formation and be used to develop drug targets. Scientists have also been able to develop reliable transgenic animal models of DIPG, which can facilitate characterization of tumor cell behavior and the investigation therapeutic targets. We have recently launched a clinical study for colleting DIPG and BSG specimens (http://clinicaltrials.gov/ct2/show/NCT01106794?term=DIPG&rank=3). Collection of such specimens (blood, urine, and tumor) will enable us to understand the molecular makeup of these tumors.
Proteomic analysis has also emerged as a valuable tool, enabling rapid, comprehensive identification of the protein profile a tumor, revealing differentially expressed proteins compared with normal brain tissue. We have previously reported a complete protein profiling of DIPG using formalin fixed postmortem specimens. However, there is a dire need for collection and analysis of fresh frozen postmortem tumor specimens, because fresh specimens are ideal for molecular analysis including DNA, RNA, microRNA and protein profiling. Based on the limited data that is available, DIPG and BSG seem to arise due to multiple molecular abnormalities, and preliminary results suggest there are subtypes of DIPG and BSG with different causative pathways. We and other scientists have recently launched clinical studies for collecting fresh tumor samples, including biopsy tissue and postmortem specimens, with the aim of analyzing molecular make up of the disease and understanding its molecular pathways (clinicaltrials.gov).
We hope to use the information acquired through these and other studies to develop new, innovative tools in the battle against DIPG and BSG, such as biologic constructs that specifically target and tumor cells to make them more sensitive to traditional radiation or chemotherapy, or molecules that shut down tumor formation pathways early in development while sparing normal brain tissue. Pediatric BSG formation is likely the result of a complex interaction of aberrant developmental and tumorigenic pathways, giving to a variety of biologically distinct tumor subtypes, including DIPG. Studies that aim to characterize the molecular basis of this disease provide the best chance of achieving a better outcome for children affected by this devastating tumor.