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Functionally assessing mutant IDH inhibitor response in glioma

Some of our work focuses on…

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Understanding interactions between mutant IDH inhibition and radiation

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Identifying how epigenetic alterations affect response to therapeutic stress

  • The mutant IDH (mIDH) inhibitor vorasidenib has been recently FDA approved for the treatment of select IDH-mutant glioma patients and has become standard-of-care. However, response to mIDH inhibitors is heterogeneous, and our understanding of how these drugs work in glioma has been severely limited by a lack of faithful animal models that respond to mIDH inhibition. To address this gap, we developed an IDH-mutant GEM model and found that it responds to mIDH inhibitor treatment. We are now using this model to perform single-cell multiomics sequencing, spatial transcriptomics, metabolomics, and methylation profiling to understand mechanisms underlying response to mIDH inhibitors in glioma. Our goal is to leverage the knowledge gained from these studies to perform functional testing to understand how IDH-mutant gliomas respond, or become resistant to, mIDH inhibitor therapy.

  • While many patients benefit from mIDH inhibitor therapy, patients inevitably progress and require second-line treatment with chemotherapy and/or radiation. While mIDH is known to cause altered response to DNA damage, it is unknown how mIDH inhibition affects efficacy of chemoradiation. We are using our IDH-mutant GEM to perform efficacy and molecular profiling studies to understand how mIDH inhibitors alter chemoradiation efficacy. We are profiling both tumor-intrinsic and immune microenvironmental effects of mIDH (and mIDH inhibition) that affect response to radiation and alkylating agents. Results from this work may inform rational concurrent and/or sequential treatment regimens combining mIDH inhibitors, radiation, and chemotherapy.

  • IDH-mutant glioma patients who are resistant to mIDH inhibition require effective alternative treatment options. Our previous work identified that DHODH inhibitors are effective in IDH-mutant gliomas due to a sensitivity to replication stress conferred by mIDH. We have since identified that inhibition of specific dioxygenases mediates this sensitivity to replication stress, and we are interested in (1) whether inhibition of these dioxygenases sensitizes to drugs that induce replication stress across non-glioma cancer types, and (2) how epigenetic alterations functionally alter replication stress response.

Select publications

Complete list:

https://pubmed.ncbi.nlm.nih.gov/?term=shi%20diana

Reviews and Editorials

  1. Tsai AC, Lin MD, Puliyappadamba VT, Junginger DM, Donovan VG, Kaplan EG, Drepanos LM, Wakimoto H, Cahill DP, Losman JA, Mouw KW, Abdullah KG, Doench JG, Nash D, Vitt D, Gege C, Kohlhof H, McBrayer SK*, Kaelin WG*, Shi DD*. KDM6 Enzymes are the Mechanistic Targets of Mutant IDH that Dictate Replication Stress Sensitivity. bioRxiv [Preprint]. 2026 Apr 17:2026.04.14.715350. doi: 10.64898/2026.04.14.715350. PMID: 42039522; PMCID: PMC13105034.

  2. Shi DD*†, Calvo Fernandez E*, Puliyappadamba VT, Lanman TA, Xiao Y, Minor M, Prost D, Lasica AB, Cai F,Neumann E, Gudipelly S, Clark LM, Nguyen Q, Peña S, Wansapura J, Kaphle P, Shipman T, Levitt M, Lin MD, Tsai AC-Y, Lee JH, Wen Z, Cahill DP, Rahman R, Haas-Kogan DA, Richardson TE, Tirosh I, Jain P, Tron AE, Nakhate V, Youssef G, Dehais C, Jacob J, Reardon DA, Miller JJ, Abdullah KG, Wen PY, DeBerardinis RJ, Xu L, Touat M, Peters KB, Gonzalez Castro L, Kaelin WG, Suvà ML†, McBrayer SK†. Vorasidenib improves response to subsequent chemoradiation in a genetically engineered mouse model of IDH-mutant glioma. Science Transl Med, In press.

  3. Sternisha AC, Li H, Gajendra K, Xiao Y, Zhao X, Traylor JI, Guo L, Jun JH, Fleishman M, Shipman T, Puliyappadamba VT, Kaphle P, Ouyang Q, Schmidt M, Shi DD, Savani MR, Tsai AC, Lee JH, Gordillo R, Garcia-Bermudez J, Kim YJ, Tso SC, Brautigam CA, Zacharias LG, Mathews TP, Xu L, Doench JG, Koduri V, Abdullah KG, Agathocleous M, Banaszynski LA, DeBerardinis RJ, Morrow EM, McBrayer SK. A transcriptional biosensor reveals mechanisms of α-ketoglutarate signaling to chromatin. Science. 2026 Jul 16;393(6808):eadx8675. doi: 10.1126/science.adx8675. Epub 2026 Jul 16. PMID: 42462028.

  4. Abdullah KG, Miki K, Edgar CK, Wu SA, Xiao Y, Savani MR, Ghoche MT, Kotermanski SE, Huang YT, Traylor JI, Guo L, Gunn K, Hicks WH, Shi DD, Tang M, Levitt MM, El-Shami M, Oken S, Manoj N, Smith BC, Puliyappadamba VT, Kaphle P, Shipman T, West RE, Liang C, Patel TR, Hatanpaa KJ, Raj P, Ma S, Ksendzovsky A, Nolin TD, Lega BC, Zinn PO, Kuhn BJ, Clark NM, Williams C, Mani DR, Gillette MA, Calzado MA, Xu L, Zacharias LG, Cai F, Mathews TP, Losman JA, Richardson TE, Levi B, Monje M, Gibson JR, Khan OH, Agnihotri S, Huber KM, Chamberland S, DeBerardinis RJ, McBrayer SK. Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth. bioRxiv [Preprint]. 2025 Sep 18:2025.09.15.676412. doi: 10.1101/2025.09.15.676412. PMID: 41000912; PMCID: PMC12458436.

  5. Xiao Y, Shi DD, Guo L, Neumann E, Levitt MM, Kaphle P, Shipman T, Li H, Cai F, Ramirez DMO, Zacharias LG, Chen Z, Lin M, Puliyappadamba VT, Chen T, Savani MR, Peña S, Wansapura J, Mathews TP, Mishra P, Kim YJ, Raj P, Richardson TE, Xu J, Mack SC, Rahme GJ, Bernstein BE, DeBerardinis RJ, Tirosh I, Suvà ML, Xu L, Abdullah KG, McBrayer SK. Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis. bioRxiv. [Preprint]. 2025 Aug 13.

  6. Savani MR, Li B, Smith BC, Gu W, Xiao Y, Baquer G, Shipman T, Oken SS, Manoj N, Zacharias LG, Puliyappadamba VT, Stopka SA, Regan MS, Levitt MM, Edgar CK, Hicks WH, Anand S, Martin-Sandoval MS, Winston R, S Patrício J, Johnson X, Tippetts TS, Shi DD, Lemoff A, Richardson TE, Zinn PO, Solmonson A, Mathews TP, Agar NYR, DeBerardinis RJ, Abdullah KG, McBrayer SK. Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice. Nat Metab. 2026 May;8(5):1124-1148. doi: 10.1038/s42255-026-01520-0. Epub 2026 Apr 29

  7. Savani MR, El Shami M, Miki K, Gattie LC, Smith BC, Hicks WH, Weiss JO, Oken SS, Katta LN, Shipman T, Ghoche MT, Zacharias LG, Martin-Sandoval MS, Montgomery EY, Xiao Y, Shi DD, Rich JN, Richardson TE, Zinn PO, Lega BC, Mathews TP, DeBerardinis RJ, Abdullah KG, McBrayer SK. Stable isotope tracing in human plasma-like medium reveals metabolic and immune modulation of the glioblastoma microenvironment. Neuro Oncol. 2026 Feb 1;28(2):415-429. doi: 10.1093/neuonc/noaf248. PMID: 41137658; PMCID: PMC12979037.

  8. Wu MJ*, Kondo H*, Kammula AV*, Shi L, Xiao Y, Dhiab S, Xu Q, Slater CJ, Avila OI, Merritt J, Kato H, Kattel P, Sussman J, Gritti I, Eccleston J, Sun Y, Cho HM, Olander K, Katsuda T, Shi DD, Savani MR, Smith BC, Cleary JM, Mostoslavsky R, Vijay V, Kitagawa Y, Wakimoto H, Jenkins RW, Yates KB, Paik J, Tassinari A, Saatcioglu DH, Tron AE, Haas W, Cahill D, McBrayer SK, Manguso RT, Bardeesy N. Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity. Science. 2024 Jul 12;385(6705):eadl6173. doi: 10.1126/science.adl6173. Epub 2024 Jul 12. PMID: 38991060; PMCID: PMC11602233.

  9. Shi DD, Lee JH, Wang AC, Khanal J, Gao W, Kaelin WG, McBrayer SK. Protocol to Establish a Genetically Engineered Mouse Model of IDH1-mutant Astrocytoma. STAR Protocols, 2023 May 6;4(2):102281.

  10. Shi DD, Savani MR, Levitt MM, Wang AC, Endress JE, Bird CE, Buehler J, Stopka SA, Regan MS, Lin Y-F, Puliyappadamba VT, Gao W, Khanal J, Evans L, Lee JH, Guo L, Xiao Y, Xu M, Huang B, Jennings RB, Bonal DM, Martin-Sandoval MS, Dang T, Gattie LC, Cameron AB, Lee S, Asara JM, Kornblum HI, Mak TW, Looper RE, Nguyen Q-D, Signoretti S, Gradl S, Sutter A, Jeffers M, Janzer A, Lehrman MA, Zacharias LG, Mathews, Losman JA, Richardson TE, Cahill DP, DeBerardinis RJ, Ligon KL, Xu L, Ly P, Agar NYR, Abdullah KG, Harris IS, Kaelin WG*, McBrayer SK.* De Novo Pyrimidine Synthesis is a Targetable Vulnerability in IDH Mutant Glioma. Cancer Cell. 2022 Sep 12;40(0):939-956.e16.

  11. McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J, Chakraborty AA, Sarosiek KA, Briggs KJ, Robbins AK, Sewastianik T, Shareef SJ, Olenchock BA, Parker SJ, Tateishi K, Spinelli JB, Islam M, Haigis MC, Looper RE, Ligon KL, Bernstein BE, Carrasco RD, Cahill DP, Asara JM, Metallo CM, Yennawar NH, Vander Heiden MG, Kaelin WG Jr. Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Hemostasis in Glioma. Cell. 2018 Sep. 175(1): 101-116.e25.

  12. McBrayer SK, Olenchock BA, DiNatale GJ, Shi DD, Khanal J, Jennings RB, Novak JS, Oser MG, Robbins AK, Modiste R, Bonal D, Moslehi J, Bronson RT, Neuberg D, Nguyen QD, Signoretti S, Losman JA, Kaelin WG Jr. Autochthonous Tumors Driven by Rb1 Loss have an Ongoing Requirement for the RBP2 Histone Demethylase. Proc Natl Acad Sci USA. 2018 Apr. 115(16): E3741-E3748.

  13. Shi DD, Trigo FF, Semmelhack MF, Wang SS. Synthesis and Biological Evaluation of bis-CNB-GABA, a Photoactivatable Neurotransmitter with Low Receptor Interference and Chemical Two-photon Uncaging Properties. J Am Chem Soc. 2014 Feb. 136(5): 1976-81.

  1. Lin M, Tsai A C-Y, Abdullah K, McBrayer SK, Shi DD. Treatment of IDH-Mutant Glioma in the INDIGO Era. npj Precis Oncol. 2024 Jul 19;8(1):149.

  2. Rahman R*, Shi DD*, Reitman ZJ*, Hamerlik P, de Groot JF, Haas-Kogan DA, D'Andrea AD, Sulman EP, Tanner K, Agar NYR, Sarkaria JN, Tinkle CL, Bindra RS, Mehta MP, Wen PY. DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology. Neuro-Oncol. 2024 Mar 22:noae072. doi: 10.1093/neuonc/noae072.

  3. Shi DD, Kaelin, WGK. The INDIGO Trial: Precision Medicine Finally Comes to Glioma. Neuro-Oncol. 2023 Sep 12; doi: 10.1093/neuonc/noad162

  4. Sharma N, Mallela AN, Shi DD, Tang LW, Abou-Al-Shaar H, Gersey ZC, Zhang X, McBrayer SK, Abdullah KG. Isocitrate dehydrogenase mutations in gliomas: A review of current understanding and trials. Neurooncol Adv. 2023 May 10;5(1):vdad053. doi: 10.1093/noajnl/vdad053.

  5. Shi DD*, Savani MR*, Abdullah KG, McBrayer SK. Emerging Roles of Nucleotide Metabolism in Cancer. Trends Cancer. 2023 May 10;S2405-8033(23)00064-X.

  6. Shi DD, Anand S, Abdullah KG, McBrayer SK. DNA Damage in IDH-mutant Gliomas: Mechanisms and Clinical Implications. J Neurooncol. 2023 May;162(3):515-523.

  7. Miller JJ, Gonzalez Castro N, McBrayer SK, Weller M, Cloughesy T, Portnow J, Andronesi O, Barnholtz-Sloan JS, Baumert BG, Berger MS, Bi WL, Bindra R, Cahill D, Chang SM, Costello JF, Horbinski C, Huang RY, Jenkins RB, Ligon KL, Mellinghoff IK, Nabors B, Platten M, Reardon DA, Shi DD, Schiff D, Wick W, Yan HJ, von Deimling A, van den Bent M, Kaelin WG, Wen PY. Isocitrate dehydrogenase (IDH) mutant gliomas: a Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions. Neuro Oncol. 2023 Jan 5;25(1):4-25.

  8. Shi DD*, Guo JA*, Hoffman HI, Su J, Mino-Kenudson M, Barth JL, Schenkel JM, Loeffler JS, Shih HA, Hong TS, Wo JY, Aguirre AJ, Jacks T, Zheng L, Wen PY, Wang TC, Hwang WL. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities. Lancet Oncol. 2022 Feb;23(20: e62-64.

  9. Pernik MN, Bird CE, Traylor JI, Shi DD, Richardson TE, McBrayer SK, Abdullah KG. Patient-derived cancer organoids for precision oncology treatment. J Pers Med. 2021 May 17;11(5): 423.