Johns Hopkins University School of Medicine, USA
Title: Local drug delivery for the treatment of brain tumors
Dr. Betty Tyler is an Assistant Professor of Neurosurgery at Johns Hopkins University. She runs a highly successful and productive laboratory and has a national reputation for stellar science in the field of translational research and local delivery of chemotherapeutic agents for brain tumor therapy. Dr. Tyler assisted in the preclinical studies that led to bringing Gliadel to brain tumor patients as a standard of care, and also evaluated the efficacy of the local delivery of Paclitaxel from a novel thermal gel depot through commercial funding. The data in these studies were the scientific bases of a multi-institutional Phase I clinical trial for patients with malignant glioma. Dr. Tyler’s collaborative efforts with scientists within Johns Hopkins as well as with researchers throughout the United States have led to multiple scientific breakthroughs. In addition to publishing over 85 peer-reviewed articles she has mentored and taught over 250 neurosurgical residents, medical students, and undergraduate students in research design, surgical techniques and statistical analysis. She directs her work toward therapeutic progress, and mentoring new scientists, with the goal of bringing effective therapies to patients with brain tumors and making a difference in the brain cancer research field.
The technology of local delivery is being utilized to target multiple pathways for brain tumor therapy. Through the combination of Gliadel, radiation therapy and oral temozolomide (TMZ), median patient survival has increased from 9 to 21 months. To further increase survival, we are exploring the local delivery of TMZ and have shown that in animal models we can achieve 37.5% long term survival. This benefit dramatically increases when combined with radiation therapy. We have also incorporated paclitaxel, a mitotic inhibitor, into a thermosensitive gel depot which provides local delivery, enhances efficacy, and limits systemic toxicity. In combination with TMZ and radiation therapy, this depot significantly increases the 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 has been efficiently incorporated and delivered using biodegradable, controlled release beads which are safe for CNS delivery. These locally delivered beads prolonged survival in the 9L rodent glioma model. Another anti-angiogenic agent, Fc-endostatin, a recombinant human endostatin conjugated to the Fc domain of IgG, showed significantly prolonged survival. Microchip direct delivery to the brain is increasingly attractive. Intracranial microdialysis has determined that the intratumoral concentration of temozolomide was not adversely effected after systemic Avastin dosing, showing that this combination may be helpful to brain tumor patients. This new technique is aiding in our assessment of the interaction between the BBB and compounds given both systemically and locally.