IDENTIFYING GENETIC DRIVERS OF GBM
Overview
GBM is a devastating disease that carries a 100% fatality rate. The current standard of care involves maximal surgical resection, followed by temozolomide (TMZ)-based chemotherapy, radiation (XRT), and tumor treating fields (TTF). Together, these measures result in a 21-month median survival (Figure 1).
One way to combat this disease would be to find ways to attack the primary tumor so that there is never a recurrence at all. In this paradigm, we would be trying to identify novel targets or mechanisms that drive the aggressiveness of the primary tumor. We would then target them with new drugs or adjunctive drugs to TMZ to eradicate it completely so that it cannot recur.
Figure 1: Current Standard of Care for GBM
Approaches
There are many different ways to approach the question of identifying genetic drivers of GBM. For example, some studies have taken the approach of looking at what genes are elevated in patients’ primary tumors. This has identified important genes like EGFR, which is amplified in approximately 57% of primary GBM tumors, suggesting that it may be involved in driving primary GBM [1]. Another approach has been to identify genes commonly mutated in GBM. This approach has identified genes like TP53, which is well known to be mutated in many cancers . However, it has also identified novel genes like IDH1 (which has a great deal of importance in patient outcomes) NF1, ATRX, PTEN, etc. [2,3]. Other newer approaches involve using functional and single cell screening techniques to even better understand which genes directly tie to function [4].
Our Work
Our lab has worked on identifying genes and mechanisms that may be important in promoting the plasticity and aggressiveness of GBM. Some examples of our projects include working on understanding the role of the dopamine receptor (DRD2) in promoting plasticity in GBM. We have elucidated the role of HIF1 in promoting migration and suppression of the T regulatory cell mediated immune response. We have additionally published on the role of MMP14, a protein involved in migration and invasiveness, and how it modulates VEGFR2, which is a common growth factor receptor, in order to promote the aggressiveness of GBM. Most recently, we have been working on functional screens for novel gene and pathway identification to better understand which genes specifically contribute to GBM’s viability.