Project 4: Novel epigenetic treatment of IDH mutant gliomas SUMMARY/ABSTRACT Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in several cancer types, including the majority of low-grade gliomas and secondary glioblastomas (GBM). Although their survival is relatively prolonged relative to patients with wild-type IDH, patients with IDH mutant gliomas still almost invariably succumb to their disease. Mutant IDH causes the aberrant production of the oncometabolite D-2-hydroxyglutarate (2HG). How 2HG contributes to glioma formation is not well-understood, but it is postulated that 2HG interferes with a number of ?-ketoglutarate dependent enzymes, including those involved in DNA demethylation. A number of lines of evidence indicate that inactivation of the demethylator TET2 could result in the DNA hypermethylation observed in many IDH mutant tumors. Treatment with selective inhibitors of mutant IDH have shown promise in acute myelogenous leukemia (AML), but results of pre-clinical studies in glioma have been mixed. Our preliminary data indicate that the transcription factor OLIG2 may be responsible for downregulating TET2 mRNA which, in combination with 2HG, potentially renders TET2 activity virtually non-existent in IDH1-mutant gliomas. As such, inhibition of mutant IDH alone would be insufficient to recoup TET2 function. It is our fundamental hypothesis that IDH mutant gliomas are dependent on repression of TET2 expression and function, and that a combined approach of inhibition of the enzymatic function of mutant IDH along with the suppression of OLIG2 will have a beneficial effect on the treatment of IDH mutant gliomas.
In Aim 1, we will validate the importance of OLIG2 in IDH mutant gliomas, using CRISPR-based gene editing in vitro and in vivo. These experiments will also determine whether IDH mutant gliomas with different background mutations, e.g., P53 mutation or 1p/19q deletion, will have different dependency on OLIG2.
In Aim 2, we will then determine whether disruption of OLIG2 alone and in combination with inhibition of mutant IDH1 function -- using the investigational compound AG-881 (a novel brain-penetrant pan-IDH mutant inhibitor) -- disrupts TET2 function and inhibits tumor growth. Since direct small molecule inhibitors of OLIG2 have not been developed, our clinical strategy will focus on the use of the FDA-approved histone deacetylase (HDAC) inhibitor, panobinostat to downregulate OLIG2. In pre-clinical studies, we will test the effects of panobinostat and other HDAC inhibitors with and without AG-881 on OLIG2 expression and TET2 function, as well as on growth of IDH mutant tumors in vitro and in vivo.
In Aim 3, we will then proceed with a 2-stage clinical study. In the first stage, we will perform a pharmacokinetic/pharmacodynamic clinical trial to verify the effects of panobinostat on OLIG2 expression in patients with IDH mutant tumors. In the second stage, we will conduct a Phase II randomized clinical trial comparing the effects of AG-881 plus panobinostat versus AG-881 alone on tumor response rate and progression-free survival (PFS). By the end of the project period, we will have verified whether our therapeutic strategy is a viable option for patients with IDH mutant glioma.

Public Health Relevance

Project 4: Novel epigenetic treatment of IDH mutant gliomas NARRATIVE Mutations in isocitrate dehydrogenase (IDH) are thought to be the main inciting genetic alteration resulting in most low-grade gliomas, some of which progress to become high-grade glioblastoma, which is almost invariably fatal. The studies proposed herein will leverage our understanding of the biology of IDH mutant gliomas to test and develop new therapies for these tumors. Specifically, we intend to deplete an important transcription factor called OLIG2 with an FDA-approved drug, panobinostat, in combination with targeting mutant IDH with the experimental drug, AG-881, which is a brain-penetrant, pan-IDH mutant inhibitor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA211015-03
Application #
9752978
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ohashi, Minori; Korsakova, Elena; Allen, Denise et al. (2018) Loss of MECP2 Leads to Activation of P53 and Neuronal Senescence. Stem Cell Reports 10:1453-1463
Goode, Benjamin; Mondal, Gourish; Hyun, Michael et al. (2018) A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat Commun 9:810
Patel, Chirag B; Fazzari, Elisa; Chakhoyan, Ararat et al. (2018) 18F-FDOPA PET and MRI characteristics correlate with degree of malignancy and predict survival in treatment-naïve gliomas: a cross-sectional study. J Neurooncol 139:399-409
Davidson, Tom B; Lee, Alexander H; Hsu, Melody et al. (2018) Expression of PD-1 by T cells in malignant glioma patients reflects exhaustion and activation. Clin Cancer Res :
Harris, Robert J; Yao, Jingwen; Chakhoyan, Ararat et al. (2018) Simultaneous pH-sensitive and oxygen-sensitive MRI of human gliomas at 3 T using multi-echo amine proton chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). Magn Reson Med 80:1962-1978
Zheng, Feibi; Zhou, Hui; Li, Ning et al. (2018) Skeletal effects of failed parathyroidectomy. Surgery 163:17-21
Xiao, Weikun; Zhang, Rongyu; Sohrabi, Alireza et al. (2018) Brain-Mimetic 3D Culture Platforms Allow Investigation of Cooperative Effects of Extracellular Matrix Features on Therapeutic Resistance in Glioblastoma. Cancer Res 78:1358-1370
Chung, Lawrance K; Lagman, Carlito; Duong, Courtney et al. (2018) Dermoid Cyst of the Prepontine Cistern and Meckel's Cave: Illustrative Case and Systematic Review. J Neurol Surg B Skull Base 79:139-150
Cheng, Lucy; Marinelli, Laura J; Grosset, Noël et al. (2018) Complete genomic sequences of Propionibacterium freudenreichii phages from Swiss cheese reveal greater diversity than Cutibacterium (formerly Propionibacterium) acnes phages. BMC Microbiol 18:19
Orozco, Luz D; Farrell, Colin; Hale, Christopher et al. (2018) Epigenome-wide association in adipose tissue from the METSIM cohort. Hum Mol Genet 27:2586

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