Northwestern University Feinberg School of Medicine

Alexander Stegh Lab

Our Work

Malignant gliomas represent the most common and lethal brain tumors that involve the cerebral hemispheres of adults. 17,500 new primary brain tumors are diagnosed in adults in the US each year, and in children, primary brain tumors are second in number only to leukemia as causes of tumor mortality. The more common astrocytic tumors are further graded as pilocytic astrocytoma, grade I; astrocytoma, grade II; anaplastic astrocytoma, grade III; and glioblastoma multiforme (GBM), grade IV. Grade IV GBM tumors culminate in death often within 12 months of diagnosis due to their propensity to infiltrate early and diffusely throughout the brain. Despite the recent introduction into clinical trials of small molecule inhibitors targeting the signature lesion, EGFR, this dismal prognosis has not changed significantly and therefore has prompted a reevaluation of all aspects of glioma drug development. Consequently, the development of reliable in vivo and in vitro model systems recapitulating genetic processes associated with GBM progression and the development of novel, highly innovative therapeutics are considered vital to the understanding and treatment of this complex and eccentric disease.

Our research program is aimed at understanding the genetic program that underlies GBM pathogenesis. We focus on the functional validation and ultimately the therapeutic modulation of novel oncogenes and tumor suppressors implicated in the genesis of malignant glioma. We generate advanced cell culture models using primary and transformed murine cells and tumor-derived human brain tumor stem cells that together with refined GBM animal models serve as in vivo testing platform for novel therapeutic strategies.

1. Development of RNAi-based nanotechnology for precision cancer medicine. Tumors are composed of highly proliferate, migratory, invasive, and therapy-evading cells. These characteristics are conferred by an enormously complex landscape of genomic, (epi-)genetic, and proteomic aberrations. The translation of these genomic discoveries into meaningful clinical endpoints requires the development of co-extinction strategies to therapeutically target multiple cancer genes, to robustly deliver therapeutics to tumor sites, and to enable widespread dissemination of therapies within tumor tissue. To address these unmet needs, in collaboration with Dr. Chad Mirkin, our laboratory developed RNAi- (i.e., siRNA and miRNA-) based Spherical Nucleic Acids (SNAs; gold nanoparticles covalently conjugated with a corona for double stranded small RNA molecules) as a gene regulation platform for the treatment of glioblastoma. SNAs showed unprecedented activities in glioma-initiating cells in vitro and patient-derived xenograft (PDX) models in vivo. In the absence of toxicity and inflammatory responses, SNAs crossed an intact blood brain barrier in non-glioma bearing mice, and via enhanced permeability and retention of the tumor-associated vasculature, effectively accumulated within gliomas. We found significant reduction in tumor burden and increase in PDX animal subject survival. SNAs represent the only nanotechnological platform that upon systemic administration accumulates in and reduces progression of intracranial gliomas, and thus, represent a powerful tool for precision cancer medicine. siRNA-based SNAs have enteed phase 0 clinical trials.

a.COVER: Jensen SA, Day ES, Ko CH, Hurley LA, Luciano JP, Kouri FM, Merkel TJ, Luthi AJ, Patel PC, Cutler JI, Daniel WL, Scott AW, Rotz MW, Meade TJ, Giljohann DA, Mirkin CA, Stegh AH. Spherical nucleic acid nanoparticle conjugates as an RNAi-based therapy for glioblastoma. Sci Transl Med. 2013; 5:209ra152. PMCID: PMC4017940. Featured in: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.

b.COVER: Kouri FM, Hurley LA, Daniel WL, Day ES, Hua Y, Hao L, Peng CY, Merkel TJ, Queisser MA, Ritner C, Zhang H, James CD, Sznajder JI, Chin L, Giljohann DA, Kessler JA, Peter ME, Mirkin CA, Stegh AH. miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes Dev. 2015. Apr 1;29(7):732-45. doi: 10.1101/gad.257394.114. PMCID: PMC4387715 Featured in:Bioportfolio, MedicalXpress, Science Daily, Machineslikeus, redOrbit, FoxNews, Neural Cell News, Science 2.0, AZoNano.com, ScienceCodex, Chicago Sun Times, Neuro-Oncology

c. Kouri FM, Ritner C, Stegh AH. miRNA-182 and the regulation of the glioblastoma phenotype – toward miRNA-based precision therapeutics. Cell Cycle. 2015. 14(24):3794-800. PMCID: PMC4825743

 

2. Metabolic reprogramming of malignant glioma. Functional genomic investigations have identified several molecular events, which enable metabolic adaptation and regulate susceptibility to targeted therapies. Among the shared metabolic characteristics is the excess production of lactate, in association with glucose and acetate oxidation, to produce energy and macromolecular precursors. Our understanding of the manner in which gene alterations affect such metabolic adaptation can reasonably be described as rudimentary. Our research focuses on Isocitrate Dehyrdogenases (IDHs).

While oncogenic mutations in IDH1 have been reported for lower grade gliomas and secondary GBM, these IDH1 mutations are rare in primary GBM. Our in silico and functional studies now indicate that non-mutated, wild-type IDH1 mRNA and protein is commonly overexpressed in primary GBM. Our molecular studies show that genetic inactivation of IDH1 decreases cancer cell growth, promotes a more differentiated, i.e., less biologically aggressive glioma cell state, increases apoptosis in response to EGFR-targeting erlotinib, and prolongs survival of animal subjects bearing GBM PDX.

a. Calvert AE, Chalastanis A, Wu Y, Hurley LA, Kouri FM, Bi Y, Kachman M, May JL, Bartom E, Hua Y, Mishra RK, Schiltz GE, Dubrovskyi O, Mazar AP, Peter ME, Zheng H, James CD, Burant CF, Chandel NS, Davuluri RV, Horbinski C, Stegh AH. Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation. Cell Rep. 2017. 19(9):1858-1873. PMID: 28564604