Central nervous system tumors are the most common form of childhood solid tumors [1
], and comprise a diverse group of tumors with different histologies, arising at various sites within the central nervous system. Although advances in neurosurgery and multi-modal therapy have led to improved patient survival for pediatric central nervous system tumors as a whole, with current 5-year survival rates of 72.5% [1
], these tumors and their treatment continue to involve significant morbidity, and ultimately, less than 50% of children will be cured. Conventional chemotherapy and radiotherapy, using the principle of increased sensitivity of cancer cells to cytotoxic damage, continue to be the mainstays of treatment for pediatric brain tumors that cannot be cured by surgery alone. Multiple studies of pediatric brain tumors demonstrated significant long-term neurologic sequelae from tumors and their treatment, such as: (1) cognitive dysfunction, (2) neuroendocrine dysregulation, and (3) developmental delays [2
]. The brains of infants and very young children, in particular, are more susceptible to neurologic and neurosensory sequelae, compared with adults, upon exposure to conventional chemotherapy and radiotherapy [4
]. Therefore, an imperative need exists to identify newer agents with a better therapeutic window that can effectively target cancer cells, while sparing normal cells in the rapidly developing pediatric brain. Furthermore, using biologic agents to delay radiotherapy in children by even a few years may reduce adverse effects of treatment.
In the past two decades, tremendous strides in the field of molecular biology have enhanced our understanding of tumori-genesis at a molecular level. A better delineation has been established for the role of proto-oncogenes and tumor suppressor genes, cell signaling, and signal transduction pathways involved in cell cycle regulation, proliferation, survival, neoplastic angiogenesis, tumor invasion, and migration. The immune mechanisms involved in tumorigenesis and in the evasion of immune surveillance have also become better understood. Key pathways for the pathogenesis of glial and embryonal tumors include: (1) Ras-mitogen-activated protein kinase; (2) phosphatidylinositol 3-kinase/protein kinase B; (3) the Janus kinase signal transducer and activator of transcription; (4) Notch; (5) the Wingless-type murine mammary virus type integration site family; and (6) Sonic Hedgehog [6
]. (The names of the last three pathways are derived from drosophila in which the genes were first characterized.) This growing body of knowledge has resulted in a new field of targeted therapeutics with the potential for directly inhibiting the pathways responsible for the tumorigenic state, while sparing normal brain cells ( and ). Furthermore, many of the newer targeted agents have a low molecular weight, which enables them to overcome the blood-brain barrier that precludes many traditional chemotherapeutic agents from entering brain tumor cells after systemic administration. Although neuro-oncology researchers are optimistic about these medications, efficacy has not yet been proven, and much work remains to be done. Moreover, although these agents are being tested as monotherapy for progressive and recurrent disease, combination therapy will likely be needed to overcome alternative pathways for tumor growth, and to account for the cytostatic nature of these agents.
Figure 1 Cell signaling pathways involved in brain tumorigenesis: Wingless-type murine mammary virus type integration site family (WNT)/β-catenin, sonic hedgehog (SHh), receptor tyrosine kinases, and downstream signal transduction pathways include Ras-mitogen-activated (more ...)
Figure 2 Cell signaling pathways and some potential therapeutic targets and agents. Akt, protein kinase B; EGFR, epidermal growth factor receptor; ERK, extracellular regulated mitogen-activated protein kinase; FTIs, farnesyl transferase inhibitors; GF, growth (more ...)
All clinicians involved in the care of children with brain tumors should be familiar with the various drug classes in our therapeutic armamentarium, and should understand their potential toxicity and value in therapy. Pediatric neurologists are especially well poised to understand and apply these drugs for rational use, because they are based on the molecular biology of the developing brain.
This review will focus on novel targeted therapeutic agents that have been in development or use for various cancers, and that are now under clinical investigation for the treatment of pediatric brain tumors (). It will describe some of the pathways targeted by these new agents and the role these pathways play in the developing brain. A companion article in this Journal will review the known neurotoxicities of these agents.
Biologic agents in pediatric CNS tumor trials