High grade malignant gliomas are the leading cause of primary brain cancer deaths, afflicting close to 20,000 patients annually in the United States alone. Targeting tumor-specific molecular biomarkers offers the potential to deliver large amounts of therapeutic radiation specifically to infiltrating tumor cells but not to the surrounding normal brain tissue. Molecular delivery of cytotoxic radioactivity to malignant gliomas has recently shown great therapeutic potential. However, one shortcoming of this approach has been the extensive radiotoxicity that occurs to the normal brain tissue when using long range beta emitters (such as 131Iodine) or shorter range alpha emitters. In contrast, Auger emitting radioisotopes only have nanometer reach and therefore can only kill cells if they can access the nucleus and intimately interact with DNA. Despite the ultra short reach, Auger emitting isotopes have a very high linear energy transfer (LET) coefficient, which is why they produce predominantly double stranded DNA breaks that are unlikely to be repaired by tumor cells. Therefore, the objective of this proposal is create a targeted molecular scaffolding that can effectively and precisely deliver large amounts of molecular targeted nano-irradiation to infiltrating glioma cells without harming adjacent normal brain. The central hypothesis behind the proposed research is that we can deliver cytotoxic quantities of 111Indium (a prototype Auger emitter) only to malignant cells expressing a tumor biomarker that we discovered to be highly expressed in malignant gliomas, but not normal brain tissue. Of great significance, our tumor associated biomarker is expressed by a significant percentage of both adult and pediatric infiltrative brainstem gliomas and medulloblastomas. Our expectations are that at the conclusion of the proposed work, we will have created a clinically relevant anti-tumor agent with potential to eradicate infiltrating tumor cells and hence prevent recurrence while causing no collateral damage to normal brain. In addition, we anticipate our system will be an ideal scaffolding to safely deliver other therapeutics to the infiltrative malignant glioma cells that are currently outside the reach of standard therapy and responsible for the inevitable recurrence of malignant high grade gliomas.

PUBLIC HEALTH RELEVANCE: High grade malignant gliomas are the leading cause of primary brain cancer deaths, afflicting close to 20,000 patients annually in the United States alone. We are proposing to create a clinically relevant anti-tumor agent with potential to eradicate infiltrating tumor cells and prevent brain tumor recurrence while causing no collateral damage to normal brain. Our approach promises to add a new type of molecular targeted therapy to the arsenal against malignant brain cancers in both adults and children.

R21NS067471

2009-09-30

2012-08-31