Alexander Stegh's Lab website

Nanotechnology
Metabolism
(Immune-)Metabolism
Me
Tumor Immunology
Early Phase Clinical Trials
MISSION
Our research program is aimed at understanding and therapeutically targeting the genetic program that underlies the pathogenesis of glioblastoma.
We apply a combination of cell/molecular biology, oncogenomic, and mouse engineering approaches, to understand fundamental mechanisms of metabolic adaptation and tumor-mediated immune suppression.
Known for our bench-to-bedside efforts to drive nanotechnologies toward clinical opportunity, we also develop novel nanotechnology-enabled approaches directed against actionable tumor and immune targets.
THE STEGH LABORATORY and THE BRAIN TUMOR CENTER at Washington University School of Medicine

Beginning in 2023, the Stegh laboratory will be housed within the new $616 million, 11-story and 609,000 square-foot, state-of-the-art Neuroscience Research Building. The building project is the largest in the history of Washington University’s School of Medicine and will span almost a block in the 200-acre Cortex Innovation Community — one of the fastest-growing business, innovation, and technology hubs in the United States. This infrastructure will enable and strengthen collaborations between academic research and industry partners, to rapidly translate fundamental science into advanced care for brain tumor patients.
PEOPLE
Mentoring the next generation of translational brain tumor scientists
KEY PUBLICATIONS
Development of Spherical Nucleic Acid Nano-Architectures
Spherical Nucleic Acids (SNAs) consists of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors.
Nanotechnology enables new ways to diagnose and treat cancer. Nanomedicines can increase payload concentration at the disease site, reduce toxicity, and enhance therapeutic effect compared to drugs in their "free" form. SNAs emerged as a new class of oligonucleotide nanotherapeutics that are currently being explored for gene regulation, the activation of innate immunity, and the development of next-generation cancer vaccines.

Building on a decade long collaboration with Dr. Chad Mirkin's group at Northwestern University and a completed phase 0 clinical trial of gene-regualtory SNAs in patients with recurrent glioblastoma (NCT03020017), ongoing efforts in the laboratory focus on the development of next generation SNA architectures conjugated with gene-regulatory siRNA oligonucleotides, DNA oligionucleotides to activate innate DNA sensing pathways, and neoantigens for glioma vaccine development.
Defining Mechanisms of Metabolic Adaptation in Gliomas and the Glioma Tumor Microenvironment

Wild-type Isocitrate Dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), NAD(P)H, and CO₂. On molecular levels, IDHs epigenetically control gene expression through effects on α-KG-dependent dioxygenases, maintain redox balance, and promote anaplerosis by providing cells with NADPH and precursor substrates for macromolecular synthesis. While gain-of-function mutations in IDH1 and IDH2 represent one of the most comprehensively studied mechanisms of IDH pathogenic effects, our studies and studies of other investigators identified wild-type IDHs as critical regulators of normal organ physiology and, when transcriptionally induced or down-regulated, as contributing to glioblastoma progression. Ongoing studies in the lab will answer the following questions:
1. How do wild-type IDHs control gene expression through chromatin and DNA modifications?
We will determine the extent of the epigenetic rewiring in wild-type IDH glioblastoma, the genes and pathways dysregulated, how these epigenetic changes support glioblastoma progression, and whether these pathways can be therapeutically targeted.

2. How do wild-type IDHs affect anti-tumor immunity?
We will determine the role of wild-type IDHs in shaping the systemic and the tumor-associated immune system, and will define the underlying mechanisms, in particular those mediated by α-KG and the ensuing effect on the regulation of immunogenic factors.

3. How does the IDH status impact progenitor cell transformation and glioma evolution?
We will determine whether and to what extent wild-type IDH1 expression in different progenitor cells (NSCs or NPCs versus OPCs) results in distinct tumor molecular and biologic properties and therapy susceptibility, using novel iPSC-derived models and inducible Cre alleles driven by NPCs or OPC-specific promoters to express or delete of wild-type IDHs in specific progenitor cell populations.

5. How can wild-type IDH1 be targeted?
We have identified small molecular inhibitors of wild-type IDH1. We will enroll these inhibitors into further preclinical testing, including detailed pharmacokinetic analysis, optimization of dosing, administration and formulation, comprehensive tumor regression analyses in advanced glioma mouse models and in vivo validation of its mechanism of action.
Defining Immunosuppression in Glioblastoma

Immunotherapies, including immune checkpoint inhibitors, can improve outcomes for patients with immunologically 'hot' tumors, but they have failed to provide survival benefits for patients with immunologically ‘cold’ tumors (i.e., low or non-T cell-inflamed), including those of glioblastoma. A limitation of using ICIs or other therapeutics to combat GBM immunosuppression is the low T cell effector response and high content of immunosuppressive myeloid cells. Our laboratory will determine precise mechanisms of immunosuppression and will identify actionable targets.

One focus in the laboratory is the study of the Activation of the Stimulator of Interferon Genes (STING) pathway, which represents one of the primary immune sensing mechanisms that bridges the innate and adaptive immune systems.
Tumor-derived double-stranded, but not single-stranded DNA is recognized by the DNA sensor cyclic GMP-AMP synthase (cGAS) in the cytosol of antigen-presenting cells. STING binds cyclic dinucleotides (CDNs), including 2′,3′–cyclic GMP-AMP (2′,3′-cGAMP), produced by cGAS in response to cytosolic DNA, and induces the expression of type I interferon and pro-inflammatory cytokines.
We will assess the importance of the cGAS-STING pathway for innate and adaptive immune responses against glioblastoma, will delineate novel mechanisms by which cGAS-activation triggers anti-tumor immunity, and will develop novel therapeutic approaches to engage this pathway, as monotherapy and when combined with other therapeutic modalities.
Developing unique Early Phase Clinical Trials for Nanomedicines

We conducted a first-in-human, window-of-opportunity phase 0 clinical trial of gene-regulatory SNAs (drug moniker: NU-0129) in patients with recurrent glioblastoma (NCT03020017), to assess SNA safety, pharmacokinetics, biodistribution, and target engagement. This clinical trial showed that intravenous infusion of SNAs, similar to results obtained in rodents and non-human primates, was safe at the dose administered and not associated with significant treatment-related toxicities. Mass spectrometry and X-ray fluorescence microscopy of resected glioblastoma patient tissue demonstrated that intravenously administered SNAs reached the patient tumor and accumulated in the cytoplasm of intraparenchymal tumor cells. SNA uptake into glioma cells was associated with a reduction in target protein expression and induction of apoptosis. These results establish SNAs as a safe, brain-penetrant precision medicine approach for the systemic delivery of siRNA oligonucleotides to intracranial tumor sites.
We are currently developing unique early phase clinical trial concepts to evaluate next-generation SNAs. In particular, we focus on the development of immunomodulatory SNAs, and the development of companion predictive and pharmacodynamic, imaging-based biomarkers.
SELECTED FUNDING
IN THE NEWS
The Guardian
What on earth is this thing and how exactly can it help me?
Read More
The Cancer Letter
Alexander Stegh named Brain Tumor Center research director at Siteman
Read More
Fierce Biotech
Northwestern U's novel gene-silencing RNA drug shows promise in glioblastoma
Read More
Our graduate students....
Meet Akanksha Mahajan, a 5th year graduate student in the Stegh lab
Read More
Dr. Stegh inducted into the College of Fellows, American Institute for Medical and Biological Engineering
Read More
MOST RECENT MANUSCRIPTS
Science Translational Medicine
Kumthekar et al., 2021
Read More
Cancers
Mahajan et al., 2022
Read More
PNAS
Kudruk et al., 2024
Read More
KEY COLLABORATORS

Chad A. Mirkin, PhD
Director of the International Institute for Nanotechnology
Rathmann Professor of Chemistry
Weinberg College of Arts & Sciences. Professor of chemical and biological engineering, biomedical engineering, materials science & engineering, and medicine at Northwestern University.
Development of Spherical Nucleic Acids nanoarchitectures
Daniel Wahl, MD, PhD
Associate Professor
University of Michigan
Defining and targeting oncogenicity of wild-type IDH1
Sriram Venneti, MD
Al and Robert Glick Family Research Professor of Pediatrics
Scientific Research Director
Carr Pediatric Brain Tumor Center
Julie Taubman Reys Scholar in Cancer
Associate Professor of Pathology
Associate Professor of Pediatrics
Defining and targeting oncogenicity of wild-type IDH1
Amy B. Heimberger, MD
Jean Malnati Miller Professor
Director of Research, Malnati Brain Tumor Center
Professor of Neurological Surgery
Development of cGAS-STING pathway agonists
Joshua Rubin, MD, PhD
Professor of Pediatrics
Washington University School of Medicine
The impact of sex differences on anti-glioma immunity
Priya U. Kumthekar MD
Associate Professor of Neurology
Northwestern University
Clinical translation of nano- medicines
CONNECT WITH US

The Stegh Laboratory

for Convergence Brain Tumor Research

The Stegh Laboratory

for Convergence Brain Tumor Research

Nanotechnology

Metabolism

(Immune-)Metabolism

Tumor Immunology

Early Phase Clinical Trials

MISSION

Our research program is aimed at understanding and therapeutically targeting the genetic program that underlies the pathogenesis of glioblastoma.

We apply a combination of cell/molecular biology, oncogenomic, and mouse engineering approaches, to understand fundamental mechanisms of metabolic adaptation and tumor-mediated immune suppression.

Known for our bench-to-bedside efforts to drive nanotechnologies toward clinical opportunity, we also develop novel nanotechnology-enabled approaches directed against actionable tumor and immune targets.

THE STEGH LABORATORY and THE BRAIN TUMOR CENTER at Washington University School of Medicine

PEOPLE

Mentoring the next generation of translational brain tumor scientists

KEY PUBLICATIONS

1. How do wild-type IDHs control gene expression through chromatin and DNA modifications?

We will determine the extent of the epigenetic rewiring in wild-type IDH glioblastoma, the genes and pathways dysregulated, how these epigenetic changes support glioblastoma progression, and whether these pathways can be therapeutically targeted.

2. How do wild-type IDHs affect anti-tumor immunity?

We will determine the role of wild-type IDHs in shaping the systemic and the tumor-associated immune system, and will define the underlying mechanisms, in particular those mediated by α-KG and the ensuing effect on the regulation of immunogenic factors.

3. How does the IDH status impact progenitor cell transformation and glioma evolution?

5. How can wild-type IDH1 be targeted?

Defining Immunosuppression in Glioblastoma

One focus in the laboratory is the study of the Activation of the Stimulator of Interferon Genes (STING) pathway, which represents one of the primary immune sensing mechanisms that bridges the innate and adaptive immune systems.

Developing unique Early Phase Clinical Trials for Nanomedicines

We are currently developing unique early phase clinical trial concepts to evaluate next-generation SNAs. In particular, we focus on the development of immunomodulatory SNAs, and the development of companion predictive and pharmacodynamic, imaging-based biomarkers.

SELECTED FUNDING

IN THE NEWS

The Guardian

The Cancer Letter

Fierce Biotech

Our graduate students....

Dr. Stegh inducted into the College of Fellows, American Institute for Medical and Biological Engineering

MOST RECENT MANUSCRIPTS

Science Translational Medicine

Cancers

PNAS

KEY COLLABORATORS

Chad A. Mirkin, PhD

Director of the International Institute for NanotechnologyRathmann Professor of ChemistryWeinberg College of Arts & Sciences. Professor of chemical and biological engineering, biomedical engineering, materials science & engineering, and medicine at Northwestern University.

Daniel Wahl, MD, PhD

Associate ProfessorUniversity of Michigan

Sriram Venneti, MD

Al and Robert Glick Family Research Professor of PediatricsScientific Research DirectorCarr Pediatric Brain Tumor CenterJulie Taubman Reys Scholar in CancerAssociate Professor of PathologyAssociate Professor of Pediatrics

Amy B. Heimberger, MD

Jean Malnati Miller Professor Director of Research, Malnati Brain Tumor CenterProfessor of Neurological Surgery

Joshua Rubin, MD, PhD

Professor of Pediatrics Washington University School of Medicine

Priya U. Kumthekar MD

Associate Professor of NeurologyNorthwestern University

CONNECT WITH US

Director of the International Institute for Nanotechnology
Rathmann Professor of Chemistry
Weinberg College of Arts & Sciences. Professor of chemical and biological engineering, biomedical engineering, materials science & engineering, and medicine at Northwestern University.

Associate Professor
University of Michigan

Al and Robert Glick Family Research Professor of Pediatrics
Scientific Research Director
Carr Pediatric Brain Tumor Center
Julie Taubman Reys Scholar in Cancer
Associate Professor of Pathology
Associate Professor of Pediatrics

Jean Malnati Miller Professor
Director of Research, Malnati Brain Tumor Center
Professor of Neurological Surgery

Professor of Pediatrics
Washington University School of Medicine

Associate Professor of Neurology
Northwestern University