The primary goal of our research program is to investigate the mechanisms associated with the malignant progression of brain tumors using techniques that can be incorporated into clinical diagnostic and patient management strategies. The current approach is to correlate in vivo physiological magnetic resonance imaging (MRI) and spectroscopic (MRS) features of human brain tumors with ex vivo measures of molecular alterations associated with tumor aggressiveness. The in vivo studies are performed on clinical MRI systems (1.5 T or 3.0T) in treatment-naïve patients, using advanced MRI and MRS techniques developed here at UCSF that interrogate the metabolic, hyperplastic, and vascular status of the tumors. During surgical removal of the tumor, tissue biopsies are collected from various regions within the tumor based on the MR features observed in the pre-surgical scans. Molecular techniques are used to probe the mitotic, morphologic, protein expression, and genetic features of the tissue biopsies to assess their aggressiveness. In addition, the tissue is scanned in a high-field magnet (11.7 T) using a technique called high-resolution magic-angle spinning (HRMAS) MR spectroscopy that yields a more detailed metabolic profile of the tissue than the in vivo MRS scans. The comparison between the molecular and HRMAS MRS profiles of the tissue biopsies helps us to understand how genetic alterations affect subsequent metabolic events in the cells. The expectation is that early molecular events that do not cause a change in tissue morphology, and are therefore invisible on conventional MRI, will exhibit a chemical signal that is distinct from surrounding normal tissue and can be detected with MRS. Acquisition of the MR spectroscopic profiles at both the systemic and cellular levels should facilitate the rapid translation of relationships discovered “in the dish” into non-invasive clinical techniques for characterizing the functional properties of tumors.

Although we are a small group, we are involved in several other research areas, each of which has the potential to become independent programs. In addition to the adult brain tumor studies described above, we have recently begun to use MRS to study brainstem gliomas in children. The location of such tumors make then inaccessible to surgery for diagnostic and treatment purposes. Because of this, we are investigating the possibility of using MRS as a surrogate marker of disease progression in these children.

A second area of research that grew out of the adult brain tumor studies, is the in-depth study of the metabolic changes that accompany malignant transformation in brain tumor cell lines using HRMAS MRS. We are currently scanning cultured cell lines of human tumors of various histologic types and grades in an effort to distinguish the metabolic changes that are specific to tumor progression from those resulting from different cell types and/or morphologic features. In a collaborative project with Dr. Maria Garcia-Martin, the cells are being used to grow intracranial tumors in rats, which are imaged in vivo and then excised for ex vivo investigation with HRMAS MRS.

We have also begun a collaboration with Dr. Krys Bankiewicz in the Department of Neurosurgery to develop MRI techniques for planning and visualizing intracranial drug delivery using convection-enhanced delivery (CED). We perform anatomic and diffusion tensor MR imaging on non-human primates to determine the geometry and interstitial volume of various brain regions. The information is used to predict the distribution of liposome-encapsulated gadolinium delivered by CED. Real-time imaging of the CED is then performed and compared with the predicted distribution. The results of this project will be useful for improving the efficacy of CED therapies that are currently being used in human clinical trials.

       Pamela Jackson - Graduate Student    Kenneth Smith - Staff Research Asst

Rabia Siddiqi - Medical Student