Small Molecule Inhibitor of Anti-Apoptotic Proteins, ABT-737, in Glioblastoma Multiforme Stem Cells
Faculty Mentor: Gary Gallia, Avadhut Joshi
Glioblastoma Multiforme (GBM) is the most common and aggressive form of intracranial malignancies. Median patient survival remains at less than 15 months despite aggressive surgical, chemotherapeutic, and radiotherapeutic treatments. In this study, we hypothesized that part of GBMs’ resistance to chemotherapeutics can be attributed to their high expression of anti-apoptotic proteins of the Bcl-2 family; therefore, targeting Bcl-2 would increase sensitivity of GBM cells to chemotherapy. To follow up on this hypothesis, we assessed the levels of Bcl-2 family proteins in GBM cell lines. We were able to conclude that Bcl-2 family proteins were significantly increased in GBMs grown as oncospheres as opposed to adherent serum-grown cell lines. Following these trials, we measured the efficacy of ABT-737, a small molecule inhibitor of these proteins. In addition, we tested the effects of ABT-737 in combination with receptor tyrosine kinase (RTK) inhibitors. The results were in accordance with our observations, as the ABT-737 treatment inhibited the GBM stem cells, but had little effect on the adherent cell lines. Furthermore, combination therapy demonstrated that sunitinib and ABT-737 synergistically inhibited GBM stem cells. These observations suggest that Bcl-2 can be targeted in GBM stem cells and warrants further investigation of ABT-737 in preclinical animal models.
How did you find your mentor for this project?
We met through a family friend. I worked during the summer of 2009.
How did you know this was the project you wanted to do?
I learned about the components involved in my project in genetics class and thought that the mechanisms were very interesting. Genetics was my first Biology class in college, so I was excited that the things that I had learned could already come into use only a month after I had finished the class.
How much time did you put into it?
It was a full-time job for the summer, but the work was very flexible. It depended on the stage of work that I was in and the amount of preparation that it took. There were some days when I would leave home at 8AM, and not be back until 9PM; and there were other days when I was done by lunch, and had extra time to look around downtown.
What academic background did you have before you started?
I had my first year of college behind me. As far as biology goes, I only had high-school and advanced placement biology completed, as well as Genetics at UMBC.
How did you hear about Undergraduate Research and Creative Achievement Day? Was the application difficult?
I heard about it when looking for grants so that I could continue my work in coming years. The application was fairly easy because I had summarized my work already for presentation at my lab.
Were you nervous about presenting your work to a large audience? How did it go?
I was more nervous about having to generalize the specifics of the work I had done without overlooking things that were very important. It went pretty well, and everyone seemed very receptive.
How much did your mentor help you with this?
The adviser my mentor assigned to me was my go-to when I needed help. A lot of people in the lab also gave me advice and let me practice with them.
What is your advice to other students about getting involved in research?
Don't be afraid to ask. The worst thing that can happen is not getting a response back, or getting a "no" outright. If you're interested enough to ask about something, chances are that you should be able to find another lab that catches your eye anyway.
What are your career goals?
I would like to study medicine, and go into surgery.
What has been the hardest part about your research?
The hardest part was understanding what I was actually doing. The literature was very dense, and everyone working in the lab was at least five or 10 years older than me. They didn't expect me to understand everything I was doing, but I wanted to study and understand everything.
What was the most unexpected thing?
I didn't expect to have finished with such good results. The project seemed very daunting at the beginning of summer, and I did not expect to have finished it by the end of summer.
My research has illustrated things I've learned in nearly every biology class I've ever taken, and some chemistry classes.
How does your research relate to your work in other classes?