Reitman Lab

Targeting Brain Tumor Mutations


Knowledge of the genomic landscape of brain tumors has exploded over the past decade. In many types of cancer outside the brain, this type of genomic knowledge has resulted in new therapies that improve patient survival by targeting mutations found in the genome of the cancer cells. However, advances in genomic characterization of brain tumors have not yet produced new survival-improving therapies for many types of brain tumors. To overcome this challenge, the Reitman Lab is investigating creative new approaches to target frequent mutations found in brain tumors. For instance, we are interested in finding novel actionable vulnerabilities associated with mutations in the promoter of the telomerase reverse transcriptase gene (TERT). TERT promoter mutations are found in more than 80% of glioblastomas, which are the most frequent and lethal primary brain tumor in adults, and the mutations confer a replicative immortality phenotype to brain tumor cells (Figure 2).

Figure 2. Identifying new approaches to target TERT promoter mutations in cancer. 
The two most frequent TERT promoter mutations found in glioblastoma are shown. The C228T mutation occurs 146 bp upstream of the start codon of TERT. The C250T mutation occurs 126 bp upstream of the start codon of TERT. Either mutation generates a de novo sequence which contains an ETS transcription factor binding motif. The new ETS binding motif aberrantly recruits transcription factors from the ETS family to the TERT promoter. This aberrantly activates TERT expression to enable replicative immortality in glioblastoma cells. Our long-term goal is to determine if targeting molecular pathways upstream of these transcription factors could be used as a cancer therapeutic approach for tumors with TERT promoter mutations. To identify such vulnerabilities, we are using genome-wide CRISPR-based screening approaches in patient-derived glioblastoma cell lines faithfully harboring TERT promoter mutations.
Figure from: Reitman ZJ, et al. Promoting a new brain tumor mutation: TERT promoter mutations in CNS tumors. Acta Neuropathol. 2013 PMID: 24217890

Representative Publications:

  1. Pooled genetic screens to identify vulnerabilities in TERT-promoter-mutant glioblastoma. Tu KJ, Stewart CE, Hendrickson PG, Regal JA, Kim SY, Ashley DM, Waitkus MS, Reitman ZJ. Oncogene. 2023 Oct;42(44):3274-3286. doi: 10.1038/s41388-023-02845-w. Epub 2023 Sep 23. PMID: 37741952.
  2. Smaller protein, larger therapeutic potential: PPM1D as a new therapeutic target in brainstem glioma. Reitman ZJ. Pharmacogenomics. 2014 Sep;15(13):1639-41. doi: 10.2217/pgs.14.123. PMID: 25410889. No abstract available.
  3. Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila. Reitman ZJ, Sinenko SA, Spana EP, Yan H. Blood. 2015 Jan 8;125(2):336-45. doi: 10.1182/blood-2014-05-577940. Epub 2014 Nov 14. PMID: 25398939.
  4. Cancer-associated isocitrate dehydrogenase 1 (IDH1) R132H mutation and d-2-hydroxyglutarate stimulate glutamine metabolism under hypoxia. Reitman ZJ, Duncan CG, Poteet E, Winters A, Yan LJ, Gooden DM, Spasojevic I, Boros LG, Yang SH, Yan H. J Biol Chem. 2014 Aug 22;289(34):23318-28. doi: 10.1074/jbc.M114.575183. Epub 2014 Jul 1. PMID: 24986863.
  5. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr, Friedman AH, Friedman H, Gallia GL, Giovanella BC, Grollman AP, He TC, He Y, Hruban RH, Jallo GI, Mandahl N, Meeker AK, Mertens F, Netto GJ, Rasheed BA, Riggins GJ, Rosenquist TA, Schiffman M, Shih IeM, Theodorescu D, Torbenson MS, Velculescu VE, Wang TL, Wentzensen N, Wood LD, Zhang M, McLendon RE, Bigner DD, Kinzler KW, Vogelstein B, Papadopoulos N, Yan H. Proc Natl Acad Sci U S A. 2013 Apr 9;110(15):6021-6. doi: 10.1073/pnas.1303607110. Epub 2013 Mar 25. PMID: 23530248.
  6. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, He Y, Bigner DD, Vogelstein B, Yan H. Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3270-5. doi: 10.1073/pnas.1019393108. Epub 2011 Feb 2. PMID: 21289278