Radiation-induced senescence in the brain microenvironment: Implications for glioblastoma recurrence and therapy

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Abstract Glioblastomas (GBM) are aggressive and radioresistant brain cancers for which better therapeutic approaches are desperately needed. GBM patients are treated with 50-60 Gy of ionizing radiation (IR), and concurrent and adjuvant chemotherapy with temozolomide (TMZ). Radiation still remains the most effective therapeutic modality for GBM, yet these tumors inevitably recur, and the recurrent tumors are highly resistant to standard therapy. Any improvement in therapy would require a better understanding of the basis of GBM recurrence and therapy resistance of the recurrent tumor. Published research from our lab with transgenic mouse models has established that IR is potently gliomagenic, and that gliomas arising after radiation exposure are marked by genomic alterations such as MET amplification which promote a cancer stem cell phenotype and radioresistance. This raises the possibility that genetic alterations in GBM cells wrought by radiation therapy could render the recurrent tumor refractory to further therapeutic intervention. Exciting new results from our lab show that radiation also promotes the development of a senescence-associated secretory phenotype (SASP) in the brain microenvironment which promotes tumor development via secretion of growth factors like HGF (ligand for MET). This suggests that radiation-induced senescence of normal brain cells in the vicinity of the tumor could alter the microenvironment to promote tumor recurrence and radioresistance. Translationally significant results from our lab show that novel “senolytic” drugs can selectively eliminate senescent astrocytes in the brain and mitigate the pro-tumorigenic effects of SASP. We hypothesize that radiotherapy-induced genetic alterations in GBM cells (e.g., MET amplification) cooperate with senescence-associated changes in the brain microenvironment (e.g., HGF secretion) to promote tumor recurrence and radioresistance. We propose to analyze if “senolytics” can selectively kill senescent brain cells arising due to radiotherapy, thereby radiosensitizing GBM and delaying tumor recurrence. There is an urgent need for experimental strategies to understand such “acquired” therapy-resistance mechanisms in GBM and develop translational approaches. We have developed novel patient-derived xenograft (PDX) and syngeneic models of GBM recurrence for this purpose. Using these models, and human GBM specimens, we will investigate (1) how MET amplification caused by radiotherapy might, via reprogramming transcription factors like SOX2 and OLIG2, generate cancer stem cells with augmented DNA repair capabilities, (2) how secretion of tumor promoting factors, like the MET ligand HGF, by senescent astrocytes might promote growth and radioresistance of GBM cells with MET amplification, and (3) how cooperation between the GBM and its senescent microenvironment can be negated with “senolytic” drugs in order to improve the outcome of GBM therapy. This project can lead to the development of effective strategies to treat GBM that take into consideration both changes to the GBM cell and the brain microenvironment during radiotherapy.