Because of the dismal prognosis for diffuse intrinsic pontine gliomas and the lack of therapeutic efficacy of current chemotherapies, innovative approaches are urgently needed.
Convection-enhanced Delivery for Diffuse Intrinsic Pontine Gliomas
The blood-brain barrier presents a significant obstacle to achieving therapeutic concentrations of systemically delivered agents in a CNS tumor. Convection-enhanced delivery is a method of local delivery that bypasses the blood-brain barrier (62). It is typically accomplished by inserting a small-bore cannula directly into a tumor and infusing the drug through the cannula. Experimental studies have led to the recognition that convection-enhanced delivery can be characterized by several common features:
- Minimized systemic effects: Systemic exposure by efflux into the vasculature is minimal.
- Increased local concentration: Local drug concentration can exceed that achieved with systemic administration by several orders of magnitude.
- Greater tissue penetration: Tissue penetration by convection-enhanced delivery is well beyond that achieved by other local delivery methods such as drug-impregnated polymers, a delivery scheme that relies on diffusion rather than bulk flow.
- Preferential distribution along white matter tracts: Distribution is preferentially along white matter tracts, a pattern remarkably reminiscent of glioma cell invasion.
- Delivery of macromolecules possible: Convection-enhanced delivery can be used to deliver macromolecules such as monoclonal antibodies or targeted toxins, a feat not possible in the brain parenchyma or tumor by systemic administration.
It is hypothesized that convection-enhanced delivery is ideally suited for the treatment of diffuse brainstem tumors on the basis of several features particular to this disease such as the tumor’s relatively compact growth pattern, its tendency to migrate along white matter fibers, the rarity of tumor-related cysts, and the lack of cavitary changes.
The safety of convection-enhanced delivery in the brainstem has been well established in rodents and non-human primates (63-71). The safety of several therapeutic agents delivered with convection-enhanced delivery into the brainstem has also been investigated, and most of the agents have proven to be safe at high concentrations (72-78). This approach has been safely used on a limited clinical basis.
Although it is clear that certain limitations exist in the application of convection-enhanced delivery for the treatment of diffuse brainstem gliomas, currently existing preclinical data are used in the design of clinical studies. Decisions in the design of these studies include the selection of an appropriate agent or agents, the surgical technique, parameters of infusion, the timing of treatment, and the methods of assessing distribution, local concentration, safety, and therapeutic efficacy. These issues, however, should not be a barrier for clinical implementation, but rather should serve as goals for phase I and II studies. Based on current preclinical data, convection-enhanced delivery may serve as the basis for a new approach in the treatment of diffuse brainstem gliomas.
Molecular Characterization of Diffuse Intrinsic Pontine Gliomas
A promising advance in the development of therapeutic agents for the treatment of diffuse intrinsic pontine gliomas is the recent molecular characterization of this tumor. Four groups independently discovered that platelet-derived growth factor (PDGF) and its receptors (PDGFR) are amplified or over-expressed in the majority of these tumors (79, 80, 81, 86, 92). Another over-expressed growth factor receptor is the epidermal growth factor receptor (EGFR) (80, 85, 87, 92). As in adult malignant gliomas, IL-13Rα2 is highly expressed in diffuse intrinsic pontine gliomas (83). These molecular abnormalities could be effective therapeutic targets. Even though biopsy of diffuse intrinsic pontine gliomas is far from being routine, when these targeted therapies based on molecular profiling of tumors come to clinical use, it would be ideal for the tumor to be pre-screened for specific targets of newly developed agents.