Interdisciplinary Initiatives Program Round 6 - 2012
Daniel Spielman, Radiology
Lawrence Recht, Neurology
Brain cancers, the most common of which is glioblastoma multiforme (GBM), represent a difficult clinical problem with most patients dying within two years of diagnosis. Although the last decade has seen progress in terms of new treatments, the field is hampered by the inability to accurately distinguish treatment effects from tumor progression with conventional tests or imaging techniques. Unlike normal tissues, which harness most of their energy needs via an oxygen-consuming process known as oxidative phosphorylation, cancers including those that involve the brain meet at least 50% of their energy needs using the much less efficient process of glycolysis, a characteristic called the Warburg effect. While this effect has intrigued scientists for over eighty years since it was first described, due to the lack of a sufficiently sensitive technology to adequately measure glucose metabolism in the living organism, it has not yet been possible to fully address whether forcing cancer tissues to use oxidative phosphorylation instead of glycolysis can reverse tumor growth. The recent development of hyperpolarized 13C magnetic resonance spectroscopy now enables the real-time investigation of these key metabolic processes in vivo. Using 13C-labeled pyruvate as a substrate allows us to quantitatively follow the in vivo fate of pyruvate, occupying a key nodal point in the metabolic pathway in which glucose is either converted to lactate or acetyl CoA (generating bicarbonate in the process). With this technology, it is possible to measure the in vivo ratio of tumor lactate/bicarbonate production, which we propose to study as a marker of cancer aggressiveness and therapeutic response.
This project represents a multidisciplinary collaboration between a group that has been on the cutting edge of the development of this technology (Dr. Spielman) with a clinician scientist (Dr. Recht) who is familiar with clinical trials as well as laboratory models of brain cancer. This partnership is already in place with initial experiments of a glioma model in which cells are transplanted into normal rat brain demonstrating the ability to robustly image and quantify the targeted metabolic pathways. We are now in position to characterize and predict treatment response in a more clinically relevant rodent tumor model in which brain cancers arise “spontaneously” in adults after in utero exposure to a mutagen. Our experiments are designed in such a way that by the end of this funding period, we will have refined this technology so as to be able to image pyruvate, lactate and bicarbonate with high sensitivity as well as to understand the capacity of the proposed metrics to predict brain tumor aggressiveness and more importantly, response to therapy. It is our ultimate goal to link treatment effects with an optimal “lactate/bicarbonate ratio” that can be used clinically not only as a measure of therapeutic efficacy, but also as a therapeutic goal for brain tumors (similar to target blood pressure for heart disease and blood glucose for diabetes) and possibly for other cancers as well. Although not part of this grant, there is a rapid path to clinical utilization of this technology given that the first clinical trial of hyperpolarized pyruvate for the assessment of prostate cancer is currently underway elsewhere, and we have pending NIH proposal to purchase the clinical machine needed to bring this technology to Stanford Hospital and Clinics.