Northwestern University Feinberg School of Medicine

Alexander Stegh Lab

Alexander H. Stegh

Biographical Sketch

Alexander Stegh was born in Hürth-Hermülheim, Germany. He obtained his Diploma in Biochemistry from the Leibniz University in Hannover, Germany. His graduate studies were carried out at the German Cancer Center in Heidelberg, Germany and the Ben-May Institute for Cancer Research, University of Chicago, USA, under the direction of Professor Marcus E. Peter culminating in a PhD degree in 2000 (Thesis title: “Effector Mechanisms of CD95/Fas/Apo-1-mediated Apoptosis”).  He completed his postdoctoral training at the Dana-Farber Cancer Institute/Harvard Medical School in the laboratory of Dr. Ronald DePinho, where he became interested in functional genomics. After promotion to instructor in 2007, he began his independent career as Assistant Professor at Northwestern University, Chicago, with appointments at the Davee Department of Neurology and the Robert H. Lurie Comprehensive Cancer Center.

Education

1992-1997 Diploma-Biochemist Leibniz University, Hannover, Germany; German Cancer Research Center, Heidelberg, Germany, Laboratory of  Peter H. Krammer, MD

Diploma Thesis: Characterization of caspase-8 activity during CD95 (Fas/APO-1)-mediated apoptosis.

Magna cum laudeSubjects: Biochemistry, Immunology, and Biophysics

1997-2000 Ph.D. German Cancer Research Center Heidelberg, Germany, Laboratory of Peter H. Krammer; MD, The Ben May Institute for Cancer Research, Laboratory of Marcus E. Peter, PhD, University of Chicago, USA

Ph.D. Thesis: Effector mechanisms of CD95 (Fas/Apo-1)-mediated Apoptosis.

Summa cum laude. Field: Cell Biology, Biochemistry, and Cancer Biology

Postdoctoral Training

2001 Postdoctoral Fellow, The Ben May Institute for Cancer Research, Laboratory of Marcus E. Peter, PhD, University of Chicago, USA

2002-2007 Research Associate, The Dana-Farber Cancer Institute/Harvard Medical School, Laboratory of Ronald A. DePinho, MD, Boston, USA

 

Academic Appointments

2007-2009 Instructor in Medicine, non-tenure track faculty appointment, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA                      

2009-Present Assistant Professor, tenure-track, Northwestern University, Davee Department of Neurology, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL

Honors and Awards

1994-1997 Undergraduate Fellowship of the Studienstiftung des Deutschen Volkes, top 1% of all undergraduate students

1999-2000 Ph.D. Program Boehringer Ingelheim Fonds, top 1% of all graduate students

2006 Claudia Adams Barr Investigator

2007 NIH K99/R00 Path to Independence Award

2009 Zell Foundation Scholar Award

2010 Sidney Kimmel Foundation Scholar Award

2011 James S. McDonnell 21st Century Award

2013 ACGT Young Investigator Award

2014 John McNicholas Glioma Scholar Award

2014 American Cancer Society Research Scholar Award

Institutional Service

2010-Present Reviewer, Scientific Review Committee (SRC), Robert H. Lurie Cancer Center

2014 Reviewer, ACS-IRG pilot grants

2010-Present Member of Steering Committee, Mouse Histology and Phenotyping Laboratory (MHPL), Northwestern University

2010-Present Candidate interviews, Driskill Graduate Program (DGP), Medical Scientist Training Program (MSTP)

2009-Present Thesis committees: Alexander Scott (Chemistry), Maya Srikanth (MSTP), Shauna Houlihan (DGP), Juno Kim (DGP), Michael Paul Plebanek (Chemistry), Anthony Sprangers (Chemistry), Alexandra Thomas (DGP), Alok Swaroop (DGP), Sonia Susan Olikara  (DGP), Jonathan Brooks Bell (MSTP), Shengshuang Zhu (MSE)

2009-Present Mentor for Cancer Biology Training Program (PI, Kathy Green)

2016-Present Mentor for the Cancer Nanotechnology Training Program (PI: Gayle Woloschak)

2015-Present Qualifying Exams, NUIN

2016-Present International Institute for Nanotechnology, member of the steering committee

2016-Present Member of task force to establish a Targeted Therapeutics Institute at Northwestern University/Feinberg School of Medicine

2017-Present Ryan Fellowship award committee

Participation in Professional Societies and Extramural Organizations

2007-Present American Association for Cancer Research (AACR)

2007-Present Society for Neuro-Oncology (SNO)

2012-Present Scientific Advisory Board, Exicure

2015-Present Member of the NCI Glioblastoma Working Group, charged with stimulating translational research and assisting in the development of clinical trial ideas for patients with glioblastoma.

Editorial and Manuscript Review Responsibilities

2010-Presentad hoc reviewer, approximately 1-2 papers per journal per year:

Clinical Cancer Research; PNAS; Journal of the American Chemistry Society; Molecular Cancer Therapeutics; British Journal of Cancer; PLOS ONE; International Journal of High Throughput Screening; Environmental Biology, International Journal of Nanotechnology; Cancer Letters; Medicinal Research Reviews; FEBS letters; Neuro-Oncology; ACS Nano; Scientific Reports; Molecular & Cellular Oncology; Molecular Biosystem; European Journal of Nanomedicine; Epigenomics;; BMC Cancer; Cell Proliferation; Molecular Carcinogenesis; Cellular and Molecular Neurobiology; Nanoscale, Elsevier (review of book proposals)

GRANT REVIEW RESPONSIBILITIES

2012-Present The Welcome Trust, ad hoc reviewer; Cancer Research UK, ad hoc reviewer; French National Research Agency (ANR), ad hoc reviewer; Israel Ministry of Science, Technology and Space, ad hoc reviewer; Swiss National Science Foundation, ad hoc reviewer; Foundation for Polish Science, ad hoc reviewer; Association for Cancer Gene Therapy (ACGT), ad hoc reviewer; NINDS, NSD-A study section, ad hoc reviewer; NINDS, Special Emphasis Panel (for the Neurological Emergency Treatment Trials Network Sites), reviewer; NINDS, ZNS1 SRB N (04), Exceptional Unconventional Research Enabling Knowledge Acceleration (EUREKA) for Neuroscience and Disorders of the Nervous System, reviewer; NIH/NCI, NCI Alliance for Nanotechnology in Cancer, Innovative Research in Cancer Nanotechnology (IRCN) (U01), reviewer ;NIH Drug Discovery and Molecular Pharmacology (DMP) study section, ad hoc reviewer.

Research Grants

Ongoing Research Support (indirect costs are listed)

NCI 1R01CA208783-A1                                                                 03/01/2016 - 2/28/2021 

(Stegh, PI)                                                                                         2.4 calendar, $360,354

Systemic RNA interference to reactivate p53 tumor suppression

Here, we will test the hypothesis that Bcl2L12 ablation by a high activity SNA conjugate 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.

NCI U54 CA199091 (Mirkin, Platanias, Co-PIs)                                      09/01/15-08/31/20 Nucleic Acid-Based Nanoconstructs for the Treatment of Cancer


Overall goal: The proposed Northwestern University (NU) CCNE will feature three projects (one discovery- based and two translational), 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. Much still remains to be learned about the genetic basis of this highly heterogeneous disease class and how it can be analyzed and treated using genetic approaches. Current treatment methodologies fall short of providing efficacious, targeted, precision 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, Co-PIs                                                                   1.20 Calendar,  $401,876

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 IDH1 to reprogram glioma metabolism.    

NCI U54 Supplement                                                                   08/01/2016 - 07/31/2017

Stegh, Lathia, Co-PIs                                                                     0.12 Calendar, $101,529

Spherical Nucleic Acids for targeting the glioma microenvironment

Here, we will test the hypothesis that IDH1 through modulation of collagen expression regulate the glioma stem cell niche, and that co-targeting of IDH1 and collagen using dual specific siCOL16A/siIDH1 SNAs reduces GIC prevalence, multipotency and tumor progression.

American Cancer Society Research Scholar Award                       07/01/14 - 06/30/18

Stegh, PI                                                                                        2.40 Calendar, $131,486

Defining and overcoming Bcl2L12-driven therapy resistance in glioma. The goal of this proposal is 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                                                                                         0.6 Calendar, $100,000

Defining and therapeutically exploring synthetic lethal interaction of IDH1 compromise. To rationally develop combinatorial treatment regimens, which will further enhance tumor suppression by IDH1 compromise, in this proposal, we will identify target genes that upon genetic inactivation promote apoptosis in IDH1 impaired cells and tumors.  We will conduct 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.

McDonnell Foundation 21st Century Science Award                      12/01/11 - 11/30/17   

Stegh, PI                                                                                        0.60 Calendar, $106,317

The Bcl2L12-miR-182 axis in Glioblastoma. Here, we will characterize miR-182 as a Bcl2L12-targeting microRNA using patient-derived cell cultures and an RCAS virus-based orthotopic  model systems.

John McNicholas Foundation grant (Lulla, Saratsis, Co-PIs)                                      01/01/2016-12/31/2018

Stegh, Project Leader                                                                      1.2 Calendar, $101,378

RNAi-based spherical nucleic acids for the treatment of pediatric high-grade gliomas (DIPGs). This proposal aims to establish proof-of-concept that SNA-directed targeting of DIPG-associated histone modifiers can inhibit progression of pediatric high-grade gliomas.

Coffman Foundation Research Grant                                        06/01/2016 -05/31/2018

Stegh, PI                                                                                          1.2 Calendar, $200,000

Small molecule inhibitors of non-mutated, wild-type IDH1 for the treatment of malignant gliomas 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.

 

Pending Research Support

NIH/NCI SPORE for translational approaches to brain cancers (Lesniak, PI)

Project 3: Using RNAi-based SNA Nanoconjugates Targeting Bcl2L12 to Promote Therapy-Induced Apoptosis in Glioblastoma                            07/01/2018 06/30/2023

Stegh, PI                                                                                          2.4 Calendar, $351,138

The goal of this project is to enroll Bcl2L12-targeting SNAs into advanced preclinical and clinical testing, emphasizing combinatorial approaches of SNAs plus TMZ and radiation therapy.

 

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 and therapeutical modulation 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 5R00CA129172                                                                                       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, Co-PIs)

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, Co-PIs)

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, Co-PIs)                                                                                             

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 a 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

(Rosen and Mirkin, Co-PIs; 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, Co-PIs)                                                                                             

Combinatorial inhibition of Bcl-2/Bcl-xL and co-activated receptor tyrosine kinases for the treatment of malignant glioma. We optimized treatment regimens using multiple RTK-inhibitors and 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

INVITED LECTURES

National

1.         Spherical Nucleic Acids as anti-glioma therapeutics. Gordon Research Conference Cancer Nanotechnology - From Basic Concepts to Clinical Applications, Waterville, ME, 2011.

2.         Toward Personalized Cancer Nanomedicine. NIH/NCI Cancer Center for Nanotechnology Excellence, Principal Investigator Meeting, Boston, MA, 2011.

3.         SNAs as anti-cancer therapeutics. International Conference and Exhibition on Nanotechnology & Nanomedicine, Omaha, NE, 2012.

4.         Bcl-2 family protein, microRNAs, and Nanotechnology – Defining and Overcoming Therapy Resistance in Malignant Gliomas. Cleveland Clinic, Cleveland, 2012.

5.         Bcl-2 family protein, microRNAs, and Nanotechnology – Defining and Overcoming Therapy Resistance in Malignant Gliomas. MD Anderson Cancer Center, 2012.

6.         Bcl2L12-targeting SNAs for the treatment of malignant glioma. NIH/NCI Cancer Center for Nanotechnology Excellence, Principal Investigator Meeting, Houston, TX, 2012.

7.         Society for Neuro-Oncology (SNO) meeting during the 2012 AACR meeting – Therapy Resistance in GBM. Chicago, IL, 2012

8.          NCI Strategic Workshop on Cancer Nanotechnology, Washington, DC, 2013

9.         How functional genomics informs nano-drug design for precision cancer medicine. TechConnect World 2014, National Harbor, MD, 2014.

10.       Metabolic adaption in cancer. Agios Pharmaceuticals, Cambridge, MA, 2015

11.       SNAs as a novel blood brain barrier permeable class of nano-therapeutics. Trans-Agency (NIH and DOD) Workshop “The Blood Brain Interface”; Bethesda, 2016.

12.       SNAs for metabolic reprogramming of malignant gliomas. NIH/NCI Cancer Center for Nanotechnology Excellence, Principal Investigator Meeting, Bethesda, 2016.

Local

1.         Bcl-2 family protein, microRNAs, and Nanotechnology – Defining and Overcoming Therapy Resistance in Malignant Gliomas. Lurie Children’s Hospital Chicago. 2012.

2.         TRIST Minisymposium ‘Developing Smart Cancer Therapies – Beyond Small Molecules’. How Functional Genomics Informs Nano-drug Design for the Treatment of Malignant Glioma. Northwestern University, Chicago, IL, 2014

3.         Metabolic reprogramming in malignant glioma. H Foundation Basic Science Symposium, Northwestern University, Chicago, 2017

MEDIA COVERAGE AND APPEARANCES

2013 WGNTV  television interview about my laboratory’s paper Jensen et al., 2013, Science Translational Medicine

2013 SWR2, German public radio interview about my laboratory’s paper Jensen et al., 2013, Science Translational Medicine

2013, 2015 Interview with various media outlets about my laboratory’s papers Jensen et al., 2013, Science Translational Medicine, and Kouri et al., 2015, Genes and Development, including US News, FoxNews, Genetic Engineering & Biotechnology News, WGNTV, Chicago Tribune, Chicago Sun-Times, WGNTV, Chemical & Engineering News, Neurology Today, Science, Nature Medicine, Molecular Therapy, The Guardian, Bioportfolio, MedicalXpress, Science Daily, Machineslikeu,s redOrbit, FoxNews, Neural Cell News, Science 2.0, AZoNano.com, ScienceCodex

TEACHING

1997 Medical School Class: Biochemistry I (University of Hannover, Germany), Laboratory/problem session instructor (10-12 Medical Students)

2001-2008 Advisory and supervisory responsibilities in laboratory settings (Ben-May Institute for Cancer Research, University of Chicago; Dana-Farber Cancer Institute). Instructed/supervised technicians and first and second year PhD  students.

2010-2012 Driskill Graduate Program, Northwestern University. Introduction into Life Science

2011 Interdepartmental Neuroscience PhD program, Northwestern University. Neurobiology of disease

2011 Medical Scientists Training Program, Northwestern University; Topics in Molecular and Translational Medicine

2012-Present Nano-boot Camp for Clinicians. Introduction into Nanomedicine; annual course offered by the International Institute for Nanotechnology

2014-Present CURE and PSOC students. Lecture on Malignant Brain and CNS cancers

2015-Present Interdepartmental Neuroscience PhD program, Northwestern University; Course Director, Neurobiology of Disease. Co-directed course, and gave lecture.

 

Trainees

Students

Alexis Ball, Undergraduate Student, University of New Mexico, CURE program, 2010

Samuel Jensen (DGP), 2009 - 2013

Timothy L. Sita (MSTP, joined mentorship with Chad Mirkin), 2012-2016

Thomas Cayton (Masters student, Biotechnology) 2013-2015

Andrea Calvert (DGP), 2011-

Jasmine May (MSTP) 2014-

Postdocs

Dr. Yongfei Wu, 2009-2014

Dr. Fotini Kouri, 2009-2016

Dr. Alexandra Chalastanis, 2010-2016

Dr. Serena Tomassini-Ghelfi, 2016- 

stegh

Alexander H. Stegh
Associate Professor
Department of Neurology