Alexander H. Stegh, PhD

Research Director of the Brain Tumor Center

Together, through a multidisciplinary and collaborative effort, we can address the fundamental challenge of improving therapeutic options for brain cancer patients and grow as leaders in the fight against brain tumors.

Dr. Stegh

Research focus

Our research program is aimed at understanding the genetic program that underlies the pathogenesis of glioblastoma, the most prevalent and malignant form of brain cancer. Applying a combination of cell/molecular biology, oncogenomic, and mouse engineering approaches, we systematically characterize novel glioma-relevant oncogenes and tumor suppressors with important roles in glioma cell survival and metabolism. In addition, my laboratory seeks to understand fundamental mechanisms of tumor-mediated immune suppression and to develop novel nanotechnology-enabled approaches directed against actionable immune targets. My group is known for its bench-to-beside efforts to drive nanotechnologies toward clinical opportunity. These efforts have resulted in the first in-human clinical trial of gene-regulatory spherical nucleic acids (SNAs) for the treatment of recurrent glioblastoma. 

View publications and collaborations »

Grants

NCI 1R01CA208783-A1
03/01/2017-2/28/2022
Stegh, PI
Systemic RNA interference to reactivate p53 tumor suppression. Here, we will test the hypothesis that Bcl2L12 ablation by a high activity Spherical Nucleic Acid (SNA) nanoconjugate increases p53 tumor suppression, reduces GBM and melanoma progression, and thus represent a novel, broadly applicable therapeutic strategy for the activation of wild-type p53 in solid cancers.

P50CA221747, SPORE for Translational Approaches to Brain Cancer (Lesniak, PI)
9/1/2018-8/31/2023
Stegh, Project 3 PI
The overall goal of Project 3 is to clinically evaluate Bcl2L12-targeting SNAs for the treatment ofGlioblastoma , and to preclinically develop combinatorial therapies of SNAs+RT, TMZ, and CCNU. The results of this proposal will provide an in-depth characterization of the Bcl2L12 oncoprotein as an actionable GBM oncoprotein, and will pave the way to successfully implement SNA-mediated, multi-modal p53 reactivation as a therapeutic approach to incorporate in clinical practice.

Convergence Science Medicine Institute, Northwestern University
04/01/2019-03/31/2023
Stegh, PI 0.6
Development of STING-agonistic Spherical Nucleic Acids (STING-SNAs) for cancer immunotherapy. Our proposed research is to develop a STING agonistic immunotherapy by targeting cGAS – thesensor of cytosolic dsDNA upstream of STING – with SNAs presenting double stranded (ds)DNA at high surface density, and to evaluate the potential of cGAS-STING-agonistic SNAs, as a novel class of immunostimulatory therapy, for use in clinical neuro-oncology. This approach is distinct from other current approaches that target the STING pathway with small molecules (including CDNs). By targeting cGAS, the strategy of using SNAs exploits the ability of cGAS to raise STING responses by delivering dsDNA and inducing the catalytic production of endogenous CDNs.

International Institute for Nanotechnology, Northwestern University
04/01/2021-03/31/2023
Stegh, PI 0.6
Development of Spherical Nucleic Acids for the immunotherapeutic treatment of malignant glioma. Here, we will develop multimodal SNA glioma vaccine conjugated with TLR9 or cGAS-agonistic DNA oligonucleotides and peptide antigens derived from R132H mutant IDH1.

Pending:

NINDS R01
Stegh, Wahl, MPIs.
Targeting wt-IDH1 for ferroptosis induction in malignant glioma.This proposal will investigate the role of non-mutated, wild-type isocitrate dehydrogenase-1 (wt-IDH1) in ferroptosis signaling in high grade glioma (HGG), and by assessing the novel wt-IDH1-specific inhibitor, 13i, developed by AbbVie, will develop a novel therapeutic strategy to target wt-IDH1 activity for the treatment of HGG.

NCI R01
Stegh, Mirkin, MPIs.
Spherical Nucleic Acids as potent cGAS agonists for the immunotherapeutic treatment of Glioblastoma. In this proposal, we will develop Spherical Nucleic Acid (SNA) nanoconjugates carrying interferon-stimulating DNA (ISD) oligonucleotides as a novel class of cGAS-STING pathway agonists. We will evaluate their anti-tumor effect as monotherapy and when combined with immune checkpoint blockade, and inhibitors of immunosuppressive adenosine signaling, and will credential SNAcGAS as a novel immunotherapeutic modality for the treatment of malignant brain tumors.

Completed Research Support:

Hofmann La Roche Research Grant
2001
Stegh, PI
Identification and molecular characterization of effector mechanisms of CD95 (Fas/Apo-1)-mediated apoptosis. Major goals of this proposal included analyses of (a) molecular mechanisms linking cytoplasmic and nuclear processes during death-receptor mediated apoptosis, and (b) the contribution of caspase activity to morphological changes during apoptosis.

Emmy-Noether Career Development Grant, German Research Foundation
2002-2004
Stegh, PI
Initial in vitro characterization of the gliomagenic activity of Bcl2L12. The major goal of this research grant was to elucidate the molecular mechanisms of Bcl2L12’s anti-apoptotic activity in glial cells, including murine cortical astrocytes and transformed human glioma cell lines.

Claudia Adams Barr Research Grant
2004-2007
Stegh, PI
In vivo characterization of the gliomagenic activity of Bcl2L12. Goal of this study was (a) to perform small-molecule inhibitor screens to specifically target Bcl2L12 as an anti-apoptotic protein in glial cells and (b) to initiate the generation of a conditional Bcl2L12 knockout mouse.

Zell Foundation Research Grant
2009-2011
Stegh, PI
The role of Bcl2L12-targeting miR-182 in glioma pathogenesis. Here, we proposed to characterize the impact of miR-182 on Bcl2L12 mRNA and protein expression in glial cell lineages, and to evaluate miR182 function in vivo using patient-derived xenografts.

NCI 5R00CA129172199
2007-2012
Stegh, PI
The role of Bcl2L12 for the genesis of malignant glioma. Here, we proposed to (a) mechanistically characterize the impact of Bcl2L12 on p53 signaling and the role of p53 pathway modulation on gliomagenesis, and (b) generate a refined mouse model for malignant glioma using a conditional Bcl2L12 knockout allele.

Sidney Kimmel Foundation for Cancer Research
2010-2012
Stegh, PI
Development and Characterization of Bcl2L12-driven GBM Mouse Models. Here, we proposed to generate and characterize xeno- and allograft models with constitutive Bcl2L12 gain and loss-of-function.

Rosenberg Family Award
2012
Stegh*, Mirkin, MPIs (*contact PI)
Toxicology and pharmacokinetics of Bcl2L12-targeting SNAs. Here, we assessed toxicology and pharmacokinetics of RNAi-functionalized nanoparticles in rodents.

American Cancer Society
2012-2013
Stegh, PI
The Role of Bcl2L13 in the genesis of malignant glioma. In this grant, we proposed to characterize the role of the novel GBM oncoprotein Bcl2L13 in therapy resistance of GBM using patient-derived cell and xenograft models.

International Institute for Nanotechnology (IIN)
2014
Stegh, PI
Pilot Project grant: Developing combinatorial treatment regimens using TMZ and spherical nucleic acids targeted to MGMT for the treatment of GBM. The goal of this pilot project was to test whether the combination of siMGMT-SNAs and the DNA alkylating drug TMZ reduce glioma progression in mice.

International Institute for Nanotechnology, The Northwestern Brain Tumor Institute
2014-2015
Stegh*, Mirkin, Raizer, MPIs (*contact PI)
Toxicity of Bcl2L12-targeting SNAs in non-human primates. We evaluated adverse side effects associated with systemic administration of SNAs targeted to Bcl2L12 in non-human primates. The Coffman Foundation, the NBTI and the IIN share the costs for this project.

Coffman Foundation, Research Grant
2014
Stegh*, Raizer, Mirkin, MPIs (*contact PI)
Toxicity of Bcl2L12-targeting SNAs in non-human primates. Here, we evaluated adverse side effects associated with systemic administration of SNAs targeted to Bcl2L12 in non-human primates. Results associated with this grant proposal served as an important milestone toward the phase 0 clinical trial of SNAs in humans. The Coffman Foundation, the NBTI and the IIN share the costs for this project.

NCI U54 CA151880
2010-2015
Mirkin* and Rosen, MPIs (*contact PI)
Stegh, Project Leader
Cancer Center for Nanotechnology Excellence (CCNE, federal support) Preclinical Validation of Polyvalent siRNA Gold Nanoparticle Conjugates as anti-Glioma Therapeutics. Here, we developed RNAi-based SNAs as a novel therapeutic agent to treat malignant brain tumors, and validated them in patient-derived orthotopic explants and genetically engineered mouse models.

Dixon Translational Science Initiative
2012 – 2015
Stegh, PI
Developing polyvalent nano-RNAi-based inhibitors of Bcl-2 signaling as anti-glioma therapeutics. Here, we proposed to preclinically evaluate polyvalent, RNAi-functionalized gold nanoparticles targeting Bcl-2/Bcl-xL as chemosensitizers for small molecule inhibitors of receptor tyrosine kinases.

Coffman Foundation, Research Grant
2012 – 2015
Stegh*, Raizer, MPIs (*contact PI)
Combinatorial inhibition of Bcl-2/Bcl-xL and co-activated receptor tyrosine kinases for the treatment of malignant glioma. We proposed to optimize treatment regimens using multiple receptor tyrosine kinase inhibitors in combination with ABT737, a Bcl-2/Bcl-xL-inactivating compound, in cell culture and xenograft models.

Alliance for Cancer Gene Therapy, Inc.
Stegh, PI
2013-2015
Defining and targeting IDH1-dependent metabolic vulnerabilities in GBM. We proposed to characterize the role of IDH1 for GBM progression, to mechanistically define the modus operandi of IDH1, and to generate IDH-1 targeting, siRNA-based SNAs.

John McNicholas Glioma Scholar Award
2014-2016
Stegh, PI
RNAi-based spherical nucleic acids for the treatment of pediatric high-grade gliomas. This proposal aimed to establish proof-of-concept that SNA-directed targeting of H3F3A mutations can inhibit progression of pediatric high-grade gliomas.

Circle of Service
2013-2015
Stegh, PI
Overcoming Bcl2L12-driven therapy resistance in malignant glioma. The goal was to develop Bcl2L12-driven mouse models, and to generate TMZ- and siBcl2L12- cofunctionalized SNAs for the treatment of GBM.

John McNicholas Foundation grant
Lulla, Saratsis, MPIs; Stegh, Project Leader
2016-2017
RNAi-based spherical nucleic acids for the treatment of pediatric high-grade gliomas (DIPGs). This proposal aimed to establish proof-of-concept that SNA-directed targeting of DIPG-associated histone modifiers can inhibit progression of pediatric high-grade gliomas.

McDonnell Foundation 21st Century Science Award
Stegh, PI
12/01/2011-11/30/2017
The Bcl2L12-miR-182 axis in Glioblastoma. Here, we characterized miR-182 as a Bcl2L12-targeting microRNA using patient-derived cell cultures and an RCAS virus-based orthotopic model systems.

American Cancer Society Research Scholar Award
07/01/2014-06/30/2018
Stegh, PI
Defining and overcoming Bcl2L12-driven therapy resistance in glioma. The goal of this proposal was to define the role Bcl2L12 for the pathogenesis of GBM in vivo using a conditional Bcl2L12 K.O. allele, and to develop antibody-functionalized, glioma-targeted SNAs.

Convergence Science Medicine Institute, Northwestern University
04/01/2016-03/31/2018
Stegh, PI
Defining and therapeutically exploring synthetic lethal interaction of IDH1 compromise. To rationally develop combinatorial treatment regimens, which will further enhance tumor suppression by wt-IDH1 compromise, in this proposal, we identified target genes that upon genetic inactivation promote apoptosis in IDH1 impaired cells and tumors. We conducted a CRISPR/Cas9-based negative selection screen for metabolic genes whose loss promotes cell death in patient-derived GICs treated with SNAs or small molecule inhibitors targeted to IDH1.

NCI U54 Supplement
Stegh*, Lathia, MPIs (*contact PI)
08/01/2016-07/31/2017
Spherical Nucleic Acids for targeting the glioma microenvironment. Here, we tested the hypothesis that wt-IDH1 through modulation of collagen expression regulate the glioma stem cell niche, and that co-targeting of wt-IDH1 and collagen using dual specific siCOL16A/siIDH1 SNAs reduces glioma stem cell prevalence, multipotency and tumor progression.

NCI U54 CA199091
Mirkin*, Platanias, MPIs (*contact PI)
09/01/2015-08/31/2021
Nucleic Acid-Based Nanoconstructs for the Treatment of Cancer
Overall goal: The proposed Northwestern University (NU) CCNE features three projects (one discovery-based and two translational projects), one core facility, and two for-profit partners united to provide novel nanotechnology-based solutions to daunting and complex issues in cancer research and treatment. Current treatment methodologies fall short of providing efficacious precision cancer therapies geared towards the individual patient. Due to their novel size-, shape and composition-dependent chemical, biological, and physical properties, nucleic-acid based nanomaterials can be used to gain access to privileged intracellular environments, discover new aspects of cancer biology and genetics, and exploit nanostructure-biomolecular interactions to create effective treatment options. Nanostructures made out of genetic materials offer the potential for fundamental learning and treatment solutions beyond what is possible with traditional therapies.

Project 2 Spherical Nucleic Acids for metabolic reprogramming of glioblastoma.
Stegh*, James, MPIs (*contact PI)
Here, we will develop an innovative, RNAi-based nanotechnology platform as a novel therapeutic agent to treat malignant brain tumors. Using PDX and genetically engineered mouse models as testing platforms, we will design, optimize and preclinically evaluate SNAs targeted to wild-type IDH1 to reprogram glioma metabolism.

Ronald and JoAnne Willens Center for Nano Oncology, Northwestern University
Stegh, PI
01/01/2019-12/31/2019
Gene-Regulatory Spherical Nucleic Acids for Glioblastoma. The overarching goals of this project are the development of gene-regulatory spherical nucleic acids (SNAs) targeted to the glioma oncogene IDH1, combined with small molecule-based IDH1 inhibitors to regulate cellular metabolism of glioma cells. Prior studies from the Stegh laboratory identified IDH1 as a critical glioma oncogene that promotes glioma progression.

Coffman Trust Research Grant
Stegh, PI
06/01/2016 -05/31/2021
Small molecule inhibitors of wild-type IDH1 for the treatment of malignant brain and lung cancers. In this proposal, we will test the hypothesis that GBM and non-small cell lung carcinomas (NSCLCs) develop metabolic vulnerabilities, which can be exploited by pharmacological inhibition of wild-type IDH1. Results from this study will pave the way for improved cancer therapy by establishing (a) wild-type IDH1 as a therapeutically targetable activity in solid cancers, and (b) the utility of wild-type-IDH1 inhibitor as adjuvant for receptor tyrosine kinase inhibitors.

P50CA221747, SPORE for Translational Approaches to Brain Cancer (Lesniak, PI)
Developmental Project, Stegh, PI
9/1/2018-8/31/2023
Harnessing metabolic vulnerabilities in wt-IDH1 Glioblastoma. The goal of this project is to preclinically evaluate a novel small molecule inhibitor targeted to wt-IDH1 for ferroptosis induction in Glioblastoma.

Awards

  • American Cancer Society Research Scholar Award, 2014 
  • John McNicholas Glioma Scholar Award, 2014
  • ACGT Young Investigator Award, 2013
  • James S. McDonnell 21st Century Award, 2011
  • Sidney Kimmel Foundation Scholar Award, 2010
  • Zell Foundation Scholar Award, 2009
  • NIH K99/R00 Path to Independence Award, 2007
  • Claudia Adams Barr Investigator, 2006
  • PhD Program Boehringer Ingelheim Fonds, top 1% of all graduate students, 1999-2000 
  • Undergraduate Fellowship of the Studienstiftung des Deutschen Volkes, top 1% of all undergraduate students, 1994-1997

Honors and leadership roles

Elected Societies:

  • American Association for Cancer Research (AACR), 2007
  • Society for Neuro-Oncology (SNO), 2007

Education

PhD, Leibniz University, Hanover, Germany
1997 – 2000

Biochemistry, Immunology, Biophysics, Leibniz University, Hanover, Germany
1992 – 1997

Fellowship

Postdoctoral Fellow, The Ben May Institute for Cancer Research; Laboratory of Marcus E. Peter, PhD; University of Chicago, IL