University of California, San Francisco
Brain Cancer
Our Research
All of our projects depend on the creation and advancement of direct infusion of drugs and therapies into the brain. We have developed a technique in which lipid-like nanoparticles and other therapeutic agents can be infused directly into brain tumors to give enhanced drug efficacy with reduced side effects. For many years, and continuing still, we have been working on development of direct drug delivery into the brain including cell transplantation, gene transfer and growth factor infusions for Parkinson's disease. Through gene therapy, we are working to eliminate this inherited lipid storage disorder by restoring the activity of the gene responsible for Niemann-Pick disease, acid sphingomyelinase. Prolonged treatment of Parkinson’s disease with L-DOPA may result in a characteristic movement disorder known as dyskinesia. By studying the effects of L-DOPA on the brain, we are developing gene therapy solutions to treat L-DOPA-induced dyskinesias. Using our image-guided delivery techniques AADC activity in the brain, important in the synthesis of several neurotransmitters, may be restored by gene therapy in patients lacking the gene for AADC.Get the Flash Player to watch this video.
This video shows our Convection-Enhanced Delivery of a drug (colored white) into a brain tumor.
Infusion of MRI-Visible Liposomes into Monkey Brainstem
The red
line indicates the position of the infusion cannula. The brainstem is the site of many inoperable brain tumors in children.
The Idea
is a uniformly fatal type of brain cancer. Despite much effort, the last 20 years have seen only a doubling of life expectancy for those with the disease to just under 2 years from diagnosis. One of the key problems with standard chemotherapy has been that systemically administered drugs do not penetrate the brain very well, and dose-limiting toxicities occur well before therapeutic concentrations of drug are achieved in the tumor. The ideal solution seemed to be injecting drug directly into tumors, thereby avoiding the systemic problems. But free drug has quite a poor persistence in the tumor mass and does not distribute well either. The initial breakthrough came from studies of drug delivery for peripheral cancers, such as breast cancer, where researchers were trying to target drugs specifically to tumor cells by attaching antibodies to the outside of engineered vesicles () that contained high concentrations of standard chemotherapy medications. We found that these liposomes dramatically improved both the half-life of the drug when infused into experimental tumors, and, as importantly, strikingly improved the distribution of drug throughout the tumor mass. The effects on tumor growth were dramatic. In rat models, we saw major prolongation of survival, and in many cases elimination of implanted human tumors.Research Implementation
These results were encouraging, but it was frustrating to consider that, once an infusion into a tumor growing inside the skull of a human being commenced, there was no way of knowing whether sufficient material was being infused or whether the infusion apparatus had been placed in the right position. Our next step forward was to graft into the drug-loaded liposomes an contrast reagent, called liposomal-gadoteridol, to allow real time visualization of intra-tumoral infusions. Because we were now able to monitor infusions, we were in a position first to gain much information about how liposomes move through the tumor mass, and also to fill tumors with drug empirically, taking account of the individual characteristics acquired by tumors as they invade the normal brain. The final technical achievement was the invention of the used to pump drug into the tumor. This cannula has a stepped outer diameter that forms a seal with the brain tissue and prevents drug from simply leaking up the outside of the cannula. We can now pump drug-loaded liposomes into tumors safely and effectively. We continue to improve the precision and safety of direct infusion of drugs and gene therapy vectors into the brain. By leveraging the basic principles of gene delivery that we mastered for the current gene therapy trial for PD [see the CBS news story on our Parkinson's Disease research], we have been able to engage advanced neurosurgical instrumentation manufacturers to help us bring forth the next generation of surgical systems. These tools will enable neurosurgeons to deliver drugs, proteins, viral vectors, and combinations of these agents into any part of the brain in the context of a fully integrated system that uses state-of-the-art control and imaging functions to make the kind of technically challenging procedures we perform now much more accessible to the medical community.
Successful Patient of MRI-Guided Infusion
Gracie, a Jack Russell Terrier, received our treatment for her brain tumor and some months later appeared tumor-free.