Glioblastoma (GBM) is the most common and deadly primary malignant brain tumor and patients are in urgent need of new, effective therapeutic strategies. One potential targeted approach that has not yet been investigated in GBM involves the homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene, a genetic alteration that occurs in approximately 50% of primary GBMs. MTAP functions in a salvage pathway that generates adenine in order to replenish intracellular nucleoside pools. Tumor cells lacking MTAP are therefore expected to have increased sensitivity to inhibitors of de novo purine synthesis. This approach has been tried in various cancer models, but has failed to progress through clinical trials due to inadequate tumor response in vivo, likely resulting from insufficient understanding of the effect of the tumor microenvironment on cellular metabolism. Furthermore, little work has been done to investigate the influence of MTAP deletion on tumor formation or growth. Our initial data suggests that purine-deprivation strategies are a viable approach to targeting MTAP-null GBM cells. We have also found that MTAP deletion in GBM results in dramatically altered metabolite levels, as well as altered epigenetic and gene expression profiles. Our objective is to establish MTAP deletion as a therapeutic target in GBM and to determine the functional consequences of this deletion in GBM pathogenesis/progression. We hypothesize that MTAP deletion leads to epigenetic and metabolic reprogramming that favors tumor development and that this alteration can be targeted therapeutically. We will test this hypothesis with the following specific aims.
Specific Aim 1 : Determine the efficacy of purine- deprivation treatment in MTAP-null GBM models. Using patient-derived GBM cell lines in vitro, we have discovered that MTAP-null GBM cells are highly sensitized to inhibition of de novo purine synthesis and that combining de novo purine synthesis inhibitors with purine transport inhibitors demonstrates potential for increased effectiveness against MTAP-null GBM in vivo. We will test and optimize this treatment strategy using primary human GBM cell lines in subcutaneous and orthotopic preclinical mouse xenograft models.
Specific Aim 2 : Determine the pathogenic contribution of MTAP deletion in GBM. We have noted that MTAP deletion is correlated with poor progression-free survival among GBM patients. Using our isogenic cell pairs we have been able to observe that this deletion contributes to a hypomethylated DNA phenotype resulting in gene activation. We have identified several differentially expressed genes through qPCR analysis and will better characterize this phenotype through gene methylation and expression arrays. We will investigate the mechanism by which these epigenetic alterations occur through focused analysis of epigenetic regulatory pathways. Additionally, we have discovered that MTAP status affects the sensitivity of GBM cells to epigenetic modifying drugs, providing a new approach to targeting this deletion in GBM. Overall, accomplishing this proposed project will shed light on the functional consequences of a common genetic alteration in GBM and will lead to novel therapeutic strategies for patients with this disease.

Public Health Relevance

Glioblastoma is the most common and deadly primary malignant brain tumor. This study explores the mechanism contributing to tumor formation and progression, and provides novel rationale and strategy for targeting a particularly common genetic alteration (MTAP deletion) that occurs during the development of these brain tumors. Because of the devastating nature of glioblastoma, novel treatments are urgently needed to improve patient outcomes, and are of critical importance to the patients and families afflicted with this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30CA206336-02
Application #
9421475
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Damico, Mark W
Project Start
2017-02-01
Project End
2019-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Duke University
Department
Pathology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Yang, Rui; Chen, Lee H; Hansen, Landon J et al. (2017) Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation. Cancer Res 77:6097-6108