Glioblastoma multiforme (GBM) is the most common and the most lethal primary brain tumor. Despite advances in a variety of therapies, survival has remained largely unchanged for more than 30 years. As a physician, I have personally witnessed the devastating morbidity and mortality associated with GBM. GBM was the principal reason that I entered Neurological Surgery. During my clinical and surgical experiences, however, I gained a deep appreciation for the lack of effect on GBM outcomes by traditional approaches. I departed my residency early with the belief that I could have a greater positive impact by making scientific advances towards understanding and then stopping GBM invasion. Through my subsequent pre- and post-doctoral studies and residency in Medical Genetics, I have steadily equipped myself with advanced skills in imaging physics, molecular biology, and proteomics. I believe I have uniquely positioned myself on a path that will enable me to use novel and multidisciplinary paradigms tempered by clinical experience to successfully approach GBM invasion. My long-term goals are to become an independent physician-scientist and to improve outcomes in patients diagnosed with GBM. My immediate goal is to complete my post-doctoral training and transition to an academic faculty position. To achieve these goals, I have designed and initiated a novel project under the guidance and mentorship of two highly productive and successful physician-scientists. Robert C. Rostomily, M.D. (mentor) leads a molecular biology laboratory that studies intracellular mechanisms of invasion in GBM. Jing Zhang, M.D., Ph.D. (co-mentor) leads a proteomics laboratory that is studying biomarkers of neurodegenerative diseases. My mentors, coupled with the unique academic and scientific environment at the University of Washington, have given me a rich and fertile setting to pursue my research, which is complementary, but unique, to their own research interests. My research proposal specifically addresses GBM invasion. The invasion of GBM into healthy brain tissues is the predominant reason for disease intractability. It is unclear why GBM tumor cells invade. However, there is compelling evidence that suggests the accumulation of specific serum proteins in the extracellular space due to disruption of the blood-brain-barrier (BBB) may govern the proliferative versus invasive phenotype. The central hypothesis of this proposal is that extravasated serum proteins (ESPs) have a direct effect on human GBM invasion. ESPs have not previously been recognized as modulators of invasion. To determine the effect of ESPs on GBM and their mechanism of action, several innovations are required. First, a novel proteomic methodology for identifying ESPs under various conditions of BBB permeability will be developed and optimized. This proteomic technique will be coupled with a novel dynamic magnetic resonance imaging (MRI) technique for measuring BBB permeability so that tissues collected for proteomic analysis can be accurately categorized. An unbiased, wide-scale technique for identifying ESPs in GBM or in any pathologic disease associated with complete or partial BBB disruption is not presently available. And finally, a state-of-the-art MRI technique known as fast bound pool fraction imaging (FBFI) will be optimized to monitor invasion of human GBM stem cells (GSCs) in an in vivo animal model. Currently available imaging techniques have been unable to capture GBM invasion in humans or in animal models of GBM. The identification of specific ESPs that actuate the invasive phenotype would deepen our understanding of GBM, while also providing new therapeutic targets that may prove more robust and/or complementary to conventional strategies. In addition, the proposed work will establish novel methodologies and technologies that have applications in a number of fields associated with neurological pathology and/or compromise of the BBB such as stroke, trauma, infection, and a variety of neurodegenerative and biochemical disorders. In summary, my unique background, established mentors, and the multitude of scientific resources at the University of Washington have provided me with an exceptional opportunity to make a significant and long- term contribution towards the improvement of outcomes in GBM. The Howard Temin Pathway to Independence Award for Cancer Research (K99/R00) will allow me to complete my post-doctoral training and provide critical support for the transition to a faculty position.
Glioblastoma multiforme (GBM) is the most common and the most lethal primary brain tumor. Despite advances in a variety of therapies, survival has remained largely unchanged for more than 30 years. The invasion of GBM into healthy brain tissues is the main reason for disease intractability. It is unclear why GBM tumor cells invade. However, there is compelling evidence that suggests the accumulation of specific serum proteins in the extracellular space due to disruption of the blood-brain-barrier may make GBM tumor cells more invasive. Serum proteins have not previously been recognized as modulators of invasion. The identification of specific serum proteins that actuate GBM cell migration would establish new therapeutic targets directed at preventing the spread of GBM tumor cells throughout the brain. By stopping the migratory behavior of GBM, therapies directed at bulk tumor growth may prove more effective and survival from this devastating disease may improve for the first time in many decades.
| Underhill, Hunter R (2017) A continuous-infusion dynamic MRI model at 3.0 Tesla for the serial quantitative evaluation of microvascular proliferation in an animal model of glioblastoma multiforme. Magn Reson Med 78:1824-1838 |
| Underhill, Hunter R; Kitzman, Jacob O; Hellwig, Sabine et al. (2016) Fragment Length of Circulating Tumor DNA. PLoS Genet 12:e1006162 |
