Research Department: Radiation Oncology Graduation Date: May 2019
Abstract:Glioblastomas (GBM) are lethal brain tumors that are typically treated with ionizing radiation (IR) and temozolomide following surgical resection. However, GBM invariably recurs with greater resistance to conventional therapies, especially radiation. As such, it is imperative to elucidate the mechanisms responsible for radioresistance, and leverage them to develop novel strategies for radiosensitization of these tumors. Ionizing radiation induces double-strand breaks (DSBs) in DNA. Our laboratory has shown that these breaks are resected by the the 5’-3’ exonuclease EXO1 which promotes accurate repair by homologous recombination (HR). EXO1 is under stringent regulation. We found that EXO1 is activated by CDK 1/2 phosphorylation strictly in the S and G2 phases. Subsequent end resection by EXO1 promotes HR, and also activates the ATR kinase. We found that ATR targets EXO1 for degradation in order to prevent hyper-resection and promote optimal repair. We, therefore, hypothesize that ATR inhibitors might augment radiotherapy of GBM via EXO1 stabilization. We find that a specific ATR inhibitor - VE822 - blocks IR-induced EXO1 degradation in a panel of GBM cell lines resulting in hyper-resection and attenuation of HR. Thus, cells treated with VE822 are unable to repair IR-induced DSBs, especially in the S and G2 phases. Attenuated HR results in striking radio-sensitization of GBM cells in vitro. Next, to test the efficacy of the drug in vivo, we generated orthotopic tumors in nude mice using patient-derived GBM neurospheres that are highly radio-resistant. We find that VE822 can cross the blood-brain barrier and, when given with IR, can block DSB repair in the intracranial tumors, attenuate tumor growth, and extend survival of tumor-bearing mice. These results indicate that ATR inhibitors could perhaps be used to augment GBM radiotherapy in the clinic.
. What does research mean to you? Research has always given me a sense of agency. Knowing that I can be productive and generate data that are significant is empowering and gives me a practical outlet for my accrued academic knowledge. As I continue to learn and work in an effort to produce novel results, I find myself increasingly enamored with the opportunity for discovery and progress. Most importantly, my time in these labs has taught me to approach the world with an inquisitive mindset, always looking to learn.
Tell us about your journey. My time in research at UTD has been so valuable and taught me so much about my love for research and discovery. However, I always wondered just how much I would be able to contribute to a lab if I were to be wholly dedicated to research, in lieu of taking classes. As such, I threw caution to the wind and decided to apply for the Green Fellowship for a chance to engage in full-time, meaningful biology research. With my decision to join the Burma Lab in Radiation Oncology, I found myself thrust into the world of cell culture and murine models. Here, I learned basic bench techniques and complex mouse surgeries. I was the proud lead on my own portion of a project and enjoyed this independence immensely. Along the way, I encountered silly mistakes and surprising successes and was so lucky to have the wonderful members of Burma Lab to support and teach me the whole time.
Advice for Future Green Fellows
Even with 40-50 hour workweeks, you still have time to participate in extracurriculars back at UTD. Use these meetings, rehearsals, gatherings, etc. as a way to stay connected to friends on campus. Some days will be exhausting and it tends to feel like there is more work to do than hours in the day. Enjoy the feeling of being busy and productive! Also, if you see some using an interesting technique, ask them to teach it to you! You may pick up unique skills along the way.