Targeting Adaptive Radioresistance of Glioblastoma

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PROJECT SUMMARY Glioblastoma (GBM) is a lethal brain cancer treated by surgery, radiotherapy, and chemotherapy. While fractionated radiation therapy (60Gy delivered over 4-6 weeks) is efficacious in killing many cancer cells, a subset gains radioresistance and survive, leading to tumor recurrence. Understanding the mechanisms underlying adaptive radioresistance may lead to new therapeutic approaches to overcome radioresistance. To decipher radioresistance mechanisms, we need sophisticated models that reflect the genetic heterogeneity of GBM, including the stem cell population, which is considered to be particularly prone to acquiring radioresistance. Till now, only limited radioresistance models have been developed and the role of glioma stem cells (GSCs) has not been properly examined. To address this gap in knowledge, I developed novel preclinical models of mouse and human GSCs that were progressively adapted to repeated irradiation. Using these models, I identified a novel resistance mechanism driven by IGF1-induced N-cadherin signaling validating my approach. To identify additional radioresistance genes, I performed a genome-wide CRISPR library screening in radioresistant human GSCs and found new candidate genes, including Syndecan 1 (SDC1). I showed that SDC1 expression is increased in 4 different radioresistant GSC lines and correlates with malignancy and poor outcome of patients with malignant glioma (TCGA database). Knockout of SDC1 in radioresistant GSCs restored radio-sensitivity, decreased IGF1R expression and suppressed IGF1R signaling. As prior literature has shown that SDC1 and IGF1R interact, these findings suggest that SDC1 and IGF1R might be components of the same radioresistance pathway. Based on this rationale, I hypothesize that increased SDC1 expression induces adaptive GBM radioresistance by activating IGF1R signaling; and that blocking SDC1-induced IGF1R activation will antagonize radioresistance and increase survival. I will test my hypothesis through the following aims: 1) examine how SDC1 confers GSC radioresistance, 2) determine how SDC1 activates IGF1R signaling, and 3) evaluate the efficacy of targeting SDC1-induced radioresistance in mouse models. My project is innovative because the role of SDC1- IGF1R-mediated signaling in GSC radioresistance has never been examined. This project will lead to the development of future my research and will become a foundation for my future career. My career plan is to systematically identify the drivers and related signaling mechanisms underlying radioresistance in GSCs. I have a dual background as a neurosurgeon and basic neuro-oncology researcher and have further secured the support of advisors and professional collaborators (see letters of support). Successful completion of this project will lead to the development of better therapies for the treatment of therapy-resistant GBM and propel my transition to an independent investigator in neuro-oncology.