Glioblastoma is the most common form of primary adult brain cancer and remains a deadly disease. The standard of care for glioblastoma involves surgical resection followed by radiation and temozolomide chemotherapy (TMZ). While Progression Free Survival (PFS) studies have revealed that nearly 80% of treated patients are responsive to TMZ at 6 months, only approximately 10% of these patients remain responsive by 24 months. We investigated whether altered microRNA (miRNA) expression during TMZ treatment contributes to acquired TMZ resistance. To this end, we profiled miRNAs in matched pre- and post- TMZ treated glioblastoma cell lines and clinical specimens. We identified one miRNA, miR-181d, which is down-regulated in response to TMZ treatment in both of these settings and profoundly influenced cellular TMZ sensitivity. miR-181d normally suppresses the expression of multiple DNA repair genes critical for TMZ resistance, including Methyl-Guanine Methyl-Transferase (MGMT) and homologous recombination (HR) genes. TMZ-induced miR-181d degradation up-regulates both processes and contributes to TMZ resistance. This proposal will characterize miRNA degradation as an acquired resistance mechanism and develop a therapy that targets this resistance.
AIM 1 proposes experiments to characterize a) the molecular mechanisms by which the DNA damage response triggers miRNA degradation and b) the relevance of this process to acquired TMZ resistance.
AIM 2 proposes experiments to a) characterize the genetic context in which miR- 181d degradation contributes to acquired TMZ resistance and b) determine the miR-181d regulated processes that contribute to this resistance.
AIM 3 is built on the premise that over-expression of miR-181d beyond cellular capacity for degradation will suppress acquired TMZ resistance; to that end, we propose a miRNA based gene therapeutic approach to address the issue of acquired TMZ resistance. INNOVATION: The proposed study to characterize TMZ-induced miRNA degradation as a novel mechanism of acquired TMZ resistance is an innovative and heretofore unexplored approach. Moreover, this proposal develops an original framework that miRNA degradation simultaneously up-regulates multiple DNA repair processes that, in turn, contribute to TMZ resistance. Finally, we propose an innovative therapeutic strategy for addressing this form of resistance. LONG-TERM OBJECTIVE: We seek to meaningfully impact the care of glioblastoma patients through the application of principles developed in the fields of DNA repair, microRNAs, and retroviral gene therapy.

Public Health Relevance

Glioblastoma is the most common form of brain cancer and remains a deadly disease. While most patients initially respond to chemotherapy, the tumors quickly acquire resistance to treatment. The study aims to develop therapies against this resistance that would help brain tumor patients better fight this disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Fountain, Jane W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
Schools of Medicine
United States
Zip Code
Ricklefs, Franz L; Alayo, Quazim; Krenzlin, Harald et al. (2018) Immune evasion mediated by PD-L1 on glioblastoma-derived extracellular vesicles. Sci Adv 4:eaar2766
Steed, Tyler C; Treiber, Jeffrey M; Brandel, Michael G et al. (2018) Quantification of glioblastoma mass effect by lateral ventricle displacement. Sci Rep 8:2827
Zanca, Ciro; Villa, Genaro R; Benitez, Jorge A et al. (2017) Glioblastoma cellular cross-talk converges on NF-?B to attenuate EGFR inhibitor sensitivity. Genes Dev 31:1212-1227
Khalil, Susanna; Fabbri, Enrica; Santangelo, Alessandra et al. (2016) miRNA array screening reveals cooperative MGMT-regulation between miR-181d-5p and miR-409-3p in glioblastoma. Oncotarget 7:28195-206
Yao, Yu; Ye, Hongxing; Qi, Zengxin et al. (2016) B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients. Clin Cancer Res 22:2778-2790
Yang, Pei; Zhang, Wei; Wang, Yinyan et al. (2015) IDH mutation and MGMT promoter methylation in glioblastoma: results of a prospective registry. Oncotarget 6:40896-906