microRNA therapies for advanced brain tumors

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ABSTRACT Each year upwards of 14,000 patients are diagnosed with Glioblastoma (GBM), the most malignant form of primary brain tumor. Surgical resection followed by radio and chemotherapies are the treatment options for GBM, but patients generally succumb to the disease. Tumor heterogeneity presents a major challenge to development of successful therapies making it increasingly apparent that the use of combination or cocktail therapies would present innovative strategies to tackle GBM. MicroRNAs (miR) are emerging as key regulators of cellular differentiation and proliferation; have been implicated in the etiology of a variety of cancers, including GBM. Numerous groups including us have demonstrated the role of microRNA modulation and their therapeutic effects on GBM tumor progression. Our data from the R00 funded research have revealed the critical role of microRNA- 124 restoration and its effect on host immunity in GBM. This in this study, we will evaluate the combinatorial effects of miR-124 modulation with immune checkpoint blockade. The effects of the proposed strategy will be mechanistically evaluated and efficacy will be evaluated using in vivo GBM models. The use of mouse models of GBM tumor resection will mimic clinical scenario of GBM care and further trigger the surgery mediated immune effects on GBM cells. Successful validation of our proposed therapeutic strategy will open avenues for novel treatment options for GBM.