(60e) New Approaches to Treating Brain Tumors

Gary Gallia, Betty Tyler, and Henry Brem

Departments of Neurosurgery, Oncology, and Biomedical Engineering

 Johns Hopkins University, Baltimore, Maryland

The technology of local delivery is being utilized to target multiple pathways for brain tumor therapy.  We will review the challenges of developing Gliadel, the first polymer drug delivery system for brain tumors.  Through combination of surgical resection, Gliadel, radiation therapy and oral temozolomide (TMZ), median patient survival for brain tumor patients has increased from 9 to 21 months. Recent clinical trials with resistance modifiers and trials with Gliadel for brain metastases have also led to improved survival. To further increase survival we have been exploring the local delivery of temozolomide and have shown that in animal glioma models we can achieve 37.5% long term survival. We have also incorporated paclitaxel, a mitotic inhibitor, into a thermo-sensitive gel depot which provides local delivery, enhances efficacy, and limits systemic toxicity. In combination with TMZ and radiation therapy this depot significantly increases long term survivors and improves median survival compared to either therapy alone. This data led to a Phase I clinical trial. Rapamycin, an MTOR inhibitor, anti-angiogenic agent and anti-proliferative agent, currently used for coronary stents, has been efficiently incorporated and intracranially delivered using biodegradable controlled release beads. We demonstrated its safety for CNS delivery as well as it significantly prolonged survival in our 9L rodent glioma model. Other anti-angiogenic agents are being explored as well, including Fc-endostatin, a recombinant human endostatin conjugated to the Fc domain of IgG, which has shown significantly prolonged survival.  Minocycline, a semi-synthetic tetracycline, has been shown to be an effective adjuvant therapy when combined with either radiation therapy or oral temozolomide, two common methods of treating glioblastoma.  Direct intracranial delivery using microchips has been a focus of our laboratory in collaboration with colleagues at MIT. Both biodegradable “passive” chips as well as microelectromechanical systems, or “active” chips, have shown efficacy in delivering chemotherapeutic agents for the treatment of both glioma as well as metastatic cancer models. Intracranial microdialysis has proven to be a very useful technique to determine real time intracranial concentrations of systemically delivered drugs. This helps to determine if effective concentrations are being reached at the site of the brain tumor. To date we have contributed to our overall objective of developing better technologies for treating brain tumor patients using locally delivered therapies.