Alexander Stegh
Washington University in St Louis, MO·Pharmacology
Glioblastoma is the most aggressive brain tumor in adults, and the immunotherapies that have transformed treatment of some other cancers have not extended survival for these patients. Two obstacles recur across this lab's projects: the tumor surrounds itself with immune cells that have been switched into a suppressive, tumor-helping state, and the tumor cells themselves are metabolically wired to resist death.
- Fields
Pharmacology
Microbiology & Immunology
Medicine & Clinical Research
- Topics
glioblastoma
high-grade glioma
wild-type IDH1
- Grants
- 3 known grants, through Jul 2029
What they work on
- Determine the cellular, epigenomic, and metabolic mechanisms by which wild-type IDH1 keeps tumor-associated myeloid cells immunosuppressive, using mice in which the enzyme is switched on or deleted only in myeloid cells via tamoxifen-induced LysM-creERT2 recombination.
- Develop treatment regimens combining 13i, a brain-penetrant wild-type IDH1 inhibitor, with immunotherapies including PD1 checkpoint blockade, measuring inflammatory myeloid states and CD8+ T cell infiltration by single-cell RNA sequencing in glioma-bearing mice.
- Test how wild-type IDH1 shapes de novo fatty acid synthesis and membrane phospholipid composition to block ferroptosis, an iron-dependent death driven by oxidized membrane lipids, in high-grade glioma cells.
- Determine how wild-type IDH1 supports GPX4-dependent lipid repair, the enzymatic removal of lipid peroxides, and thereby protects glioma cells from ferroptotic death.
- Test whether genetic or pharmacological inactivation of wild-type IDH1 amplifies ferroptosis triggered by radiation therapy and immune checkpoint blockade and slows high-grade glioma progression in mouse models.
- Optimize spherical nucleic acids, nanoparticles densely coated with interferon-stimulating DNA, for maximal activation of the cGAS-STING innate DNA-sensing pathway in cultured cells and in mice.
- Assess the anti-tumor effect of lead spherical nucleic acid cGAS agonists in glioblastoma models, alone and combined with checkpoint blockade and inhibitors of adenosine signaling, a pathway tumors use to suppress immunity.
More about the research
Three projects converge on these problems from different angles. Two center on a metabolic enzyme, wild-type isocitrate dehydrogenase-1 (wt-IDH1), which the group found is overproduced in about two-thirds of glioblastomas that lack the familiar IDH1R132H mutation; a third builds nanoparticle drugs that switch on the innate immune system's DNA-sensing alarm inside brain tumors.
Why it matters
Patients with glioblastoma have few effective options and have not benefited from the immunotherapies that help other cancers. These projects could supply two new approaches: a brain-penetrant inhibitor of wild-type IDH1 that may both strip tumor cells of their defense against ferroptotic death and flip tumor-associated myeloid cells into an anti-tumor state, and DNA-coated nanoparticles that awaken the body's innate DNA-sensing alarm inside brain tumors. Either could be combined with checkpoint inhibitors or radiation to make these tumors treatable.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Targeting Myeloid Metabolism to Reprogram the Tumor Microenvironment of Glioblastoma
NIH · Aug 2025 – Jul 2029
Spherical Nucleic Acid nano-architectures as first-in-class cGAS agonists for the immunotherapeutic treatment of Glioblastoma.
NIH · Sep 2022 – Aug 2027
Inhibition of wild-type IDH1 as a ferroptosis-inducing therapeutic approach for the treatment of malignant glioma.
NIH · Sep 2022 – Jun 2027
Closest labs
Dolores Hambardzumyan
University of Pennsylvania, PA·Microbiology & Immunology
Map how glioblastoma subtype and location shape monocyte and neutrophil infiltration, using single-cell RNA sequencing, spatial multiomics and multiplex flow cytometry in mice carrying human tumor-driving mutations.
Jennifer Yunyan Zhang
Duke University, NC·Microbiology & Immunology
Test whether UBE2N's enzyme activity and its partner UBE2V1 maintain normal epidermis and skin immune balance, using conditional genetic mouse models, single-cell transcriptomics and proteomics.
Jessalyn Ubellacker
Harvard University, MA·Biochemistry
Test whether melanoma cells depend on making N-acylglycines, a class of lipid molecules, to survive in lymph nodes, and whether blocking this pathway reduces their survival, using patient-derived xenograft and mouse melanoma models.
The school
Washington University in St Louis: 97 labs on PI Pages, $1.2B a year on research, 365 research doctorates a year.
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