Understanding mechanisms of radiation resistance in glioblastoma for novel therapeutics

In our lab we are trying to address the fundamental issue of radiation resistance and recurrence in glioblastoma multiforme (GBM). GBM is the most aggressive and malignant primary brain tumor with median overall survival of barely 18 months. Despite aggressive radiotherapy recurrence in GBM is inevitable making GBM the most difficult brain tumor to treat. We have shown that GBM recurrence is due to the residual disease cells also called persister cells that survive radiotherapy. Therefore, it is imperative to eliminate residual/persister cells to prevent recurrence and improve patient outcome. However, due to lack of patient biopsies post-surgery and radiotherapy, the molecular mechanisms leading to persister cell survival are not known. To overcome this lacune, we have developed a cellular model from primary culture pf patient samples and PDOX (patient derived orthotopic xenograft) model in mice that mimic clinical scenario of GBM resistance and recurrence. Using these model systems, we are able to capture the rare population of residual/ persister cells that survive radiotherapy and are responsible for relapse. We take multi-pronged approach to delineate molecular mechanisms of radiation survival in persisters and recurrent cells to enable us to target these cells for GBM therapeutics. In this talk, I will discuss recent findings from our lab that describe novel mechanisms of DNA damage repair pathway modulation in residual cells that help them survive radio therapy. Inhibition of these pathways provide persister/residual cell-specific radio sensitization and expand the therapeutic window for DNA damage response-targeted agents used in combination with radiotherapy. (author)