The goal of this project is to develop GABP as a therapeutic target to reverse immortality of tumors harboring a mutant telomerase reverse transcriptase (TERT) promoter. TERT promoter mutation is the third most common mutation in human cancer, affecting over 80% of GBM and oligodengroglioma (OD). Due to a lack of TERT transcription in somatic cells, telomeres shorten with each successive cell division until they reach a critical level that triggers senescence and limits cell lifespan. Reactivation of TERT expression overcomes these barriers, enabling tumor cells to proliferate indefinitely. Although proteins controlling mutant TERT promoter reactivation and tumor cell immortalization may be ideal therapeutic targets, the exact identity of these molecules remained unknown. We discovered that a single ubiquitously expressed transcription factor, GABP, uniquely bound to the mutant TERT promoter and drove TERT reactivation in TERT-promoter-mutant glioma and other cancers. GABP binds DNA as a heterodimer or a heterotetramer which regulate functionally distinct transcriptional programs. In our preliminary data, we identify a specific heterotetramer forming GABP?1 isoform (GABP?1L) that is dispensable in normal cells but may be critical for mutant TERT promoter activation and tumor cell immortalization. If the mutant TERT promoter is uniformly present throughout each tumor, and if GABP?1L modulation leads to tumor cell death while sparing normal cells, the GABP pathway may represent a new therapeutic option for mutant TERT promoter-driven malignancies. We will test this hypothesis with three specific aims:
In Aim 1, we will determine the extent to which the TERT promoter mutation is clonal at diagnosis and recurrence. We devised a robust system to collect and analyze clonality in 10 spatially mapped samples from each GBM and OD, representing maximal tumor geography.
In Aim 2, we will determine if the GABP heterotetramer is required to maintain cellular immortality in TERT promoter mutant CNS tumors. We will use CRISPR-Cas9 genetic targeting of the GABPB1L isoform to determine the consequences on TERT expression, telomere length, cell viability and tumor formation. The transcriptome effects and death mechanism of GABP?1L deficient tumor cells will be determined to identify vulnerabilities to exploit with existing therapies.
In Aim 3, we will identify therapies that will increase cell death in TERT promoter mutant tumors deficient in GABP?1L. In our preliminary data, failure of GBM cells to fully activate TERT expression by a GABP heterotetramer culminates in telomere dysfunction and DNA damage. We will perform a focused, exploratory screen of DNA damaging and DNA damage response-inhibiting agents on GABP?1L deficient cells to identify therapies that will increase cell death and decrease tumor formation. These studies could establish the GABP?1L isoform as a valuable therapeutic target specifically for TERT promoter mutant CNS tumors, and potentially many others. In parallel, we will advance drug discovery and development efforts towards small molecule inhibitors of different GABP subunits with industry partners Telo Therapeutics and GlaxoSmithKline.
PROJECT RELEVANCE Brain tumors and many other tumor types achieve immortality, the ability to proliferate indefinitely, through a mutation in the promoter of the TERT gene, the third most common mutation in human cancer. We discovered the protein that turns on the mutant TERT promoter, and believe it may be the key to tumor cell immortality. We will test this protein as a new therapeutic target to reverse tumor immortality specifically in TERT promoter mutant cancer cells, sparing normal cells.
|Ostrom, Quinn T; Kinnersley, Ben; Armstrong, Georgina et al. (2018) Age-specific genome-wide association study in glioblastoma identifies increased proportion of 'lower grade glioma'-like features associated with younger age. Int J Cancer 143:2359-2366|
|Pekmezci, Melike; Stevers, Meredith; Phillips, Joanna J et al. (2018) Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway. Acta Neuropathol 135:485-488|
|Behr, Spencer C; Villanueva-Meyer, Javier E; Li, Yan et al. (2018) Targeting iron metabolism in high-grade glioma with 68Ga-citrate PET/MR. JCI Insight 3:|
|Taylor, Jennie W; Parikh, Mili; Phillips, Joanna J et al. (2018) Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma. J Neurooncol 140:477-483|
|Luks, Tracy L; McKnight, Tracy Richmond; Jalbert, Llewellyn E et al. (2018) Relationship of In Vivo MR Parameters to Histopathological and Molecular Characteristics of Newly Diagnosed, Nonenhancing Lower-Grade Gliomas. Transl Oncol 11:941-949|
|Viswanath, Pavithra; Radoul, Marina; Izquierdo-Garcia, Jose Luis et al. (2018) 2-Hydroxyglutarate-Mediated Autophagy of the Endoplasmic Reticulum Leads to an Unusual Downregulation of Phospholipid Biosynthesis in Mutant IDH1 Gliomas. Cancer Res 78:2290-2304|
|An, Zhenyi; Knobbe-Thomsen, Christiane B; Wan, Xiaohua et al. (2018) EGFR Cooperates with EGFRvIII to Recruit Macrophages in Glioblastoma. Cancer Res 78:6785-6794|
|Mancini, Andrew; Xavier-Magalhães, Ana; Woods, Wendy S et al. (2018) Disruption of the ?1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner. Cancer Cell 34:513-528.e8|
|Disney-Hogg, Linden; Sud, Amit; Law, Philip J et al. (2018) Influence of obesity-related risk factors in the aetiology of glioma. Br J Cancer 118:1020-1027|
|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|
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