MECHANISMS OF RESISTANCE
Overview
The current standard of care for GBM 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). The big reason behind this recurrence is thought to be the intrinsic therapeutic resistance of the tumor. This means that although we give it extremely toxic therapies, some cells are able to survive and resist the therapy. Therefore, our goal is to better understand what mechanisms drive that resistance.
As we discuss elsewhere, CSCs may be one subpopulation that is contributing to this resistance and recurrence. However, there are likely many other pathways that are changing in order to respond to the therapeutic stress. It is all these pathways acting together that allow GBM to evade therapy and recur. Thus, identifying some of these pathways and targeting them directly, in conjunction with TMZ, may allow us a new path for identification of therapies that could treat recurrence.
Figure 1: Current Standard of Care for GBM
Approaches
There are many different ways to approach the question of identifying mechanistic changes after TMZ therapy. One gene that has been commonly identified as being involved in TMZ resistance is MGMT. This is a gene that is involved in DNA repair. TMZ alkylates DNA and creates DNA breaks. MGMT repairs those breaks. Therefore, if MGMT is being highly expressed by the cell, it is able to repair the breaks and therefore resist TMZ. In contrast, if MGMT is methylated, or repressed, the cell is not able to resist TMZ therapy as effectively. This has borne out in clinic as well - patients who have MGMT methylation tend to have tumors that are responsive to TMZ and therefore have better overall outcomes (1). This is one great example, but there are many other proteins that have been shown to be elevated after TMZ and likely play a role as well, including proteins like Notch1 and growth factors like VEGF (2). One therapeutic strategy that has come out of this is the drug Avastin, which targets VEGF specifically, and prevents formation of blood vessels. Clinical trials of Avastin have shown that it increases progression-free survival but does not change overall survival (3). Continuing to study these mechanisms will likely allow identification of even better therapeutic strategies over time.
Our Work
Our lab has worked on a number of projects related to understanding what pathways are changing after therapeutic stress. A few examples of our work are listed below and you can see more in our entire publication list.