Functional and Therapeutic Relevance of MTAP Deletion in Glioblastoma

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2019

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Abstract

Primary glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, with a median patient survival of only 15 months from the time of diagnosis. GBM is particularly challenging to treat due to its aggressive and invasive nature, and has proven resistant to therapeutic advances, with no significant improvement in outcomes over the past several decades. Understanding of the molecular characteristics of GBM, however, has improved dramatically, with genetic, epigenetic, and transcriptomic classifications now able to divide GBM into subtypes that provide prognostic information and guide the organization of clinical trials. One of the most frequent genetic alterations that has been identified in GBM is homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene, which occurs in 50% of all GBM cases. Despite its common occurrence, it is unclear what contribution MTAP loss makes in the pathogenesis of GBM or whether this genetic alteration can be used as a therapeutic target.

MTAP is a metabolic enzyme in the salvage pathway of adenine and methionine and its absence results in the accumulation of its metabolic substrate, methylthioadenosine (MTA), within and around tumor cells. MTA is known to inhibit activity of methyltransferases, raising the possibility that MTA accumulation is interfering with regulatory processes within the cell.

We utilized patient-derived GBM cell lines in vitro and GBM xenografts in vivo, to characterize consequence of MTAP deletion in GBM through analysis of DNA methylation, gene expression, and response to therapeutic agents. We show that MTAP loss promotes the formation of glioma stem-like cells through epigenomic dysregulation. We show these epigenetic changes influence gene expression patterns and alter the sensitivity to epigenome-modifying drugs. We also demonstrate that MTAP-null GBM cells are more tumorigenic in experimental models and that patients with MTAP deletion have poor disease outcomes. Finally, we show that targeting metabolic liabilities of MTAP-null cells through inhibition of de novo purine synthesis specifically depletes the therapy-resistant, stem-like cell subpopulation of GBM.

As the final component of this work, we explore the impact of MTA accumulation in the tumor microenvironment. We found that MTA alters the function of immune cells through adenosine receptor signaling, suggesting that modulation of adenosine receptor signaling in GBM may improve the native immune response and the efficacy of immunotherapeutics in the treatment of this disease.

This work thus establishes MTAP deletion as a pathogenic genetic alteration in the process of gliomagenesis by illustrating it’s contribution to the formation of the cancer cell epigenomic landscape, stemness characteristics, growth, and response to therapeutic agents.

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Hansen, Landon John (2019). Functional and Therapeutic Relevance of MTAP Deletion in Glioblastoma. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/18650.

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