Issue No. 30, July 2020
VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine and external affiliate members focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.      
Lumefantrine: an anti-malarial drug shows promise for glioblastoma treatment
 
Research from Dr. Paul B. Fisher and colleagues demonstrates that lumefantrine, an FDA-approved anti-malarial drug, may serve as a therapy for glioblastoma multiforme (GBM) that is resistant to the standard of care involving radiation and temozolomide.
 
  • RNAseq analysis identified heat shock protein B1 (HSPB1) as a prominent upregulated HSP in GBM and in radio/TMZ-resistant GBM.
  • Expression of HSPB1 is regulated by the friend leukemia integration 1 transcription factor (Fli-1), which binds to the 5-kb upstream regulatory region of the HSPB1 gene.
  • Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a prospective Fli-1 inhibitor.
  • Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ resistant GBM and inhibited tumor growth without toxicity in vivo in an orthotopic brain tumor model.
  • Targeted inhibition of Fli-1/HSPB1 by lumefantrine also inhibited Fli-1/HSPB1-mediated EMT and ECM remodeling signaling axes in GBM.
  • These preclinical studies provide a solid rationale for Fli-1/HSPB1 inhibition with lumefantrine, an FDA-approved drug as a novel approach for GBM management.
 
Glioblastoma multiforme (GBM) is the most aggressive type of brain cancer with a five-year survival rate of less than 6 percent, and no current therapies prevent recurrence. Current standard of care includes radiation therapy and a chemotherapeutic drug called temozolomide, can marginally extend the lives of patients with GBM, however, patients frequently develop resistance to these therapeutics. New research from Dr. Paul B. Fisher and colleagues demonstrated that lumefantrine, an FDA-approved drug used to treat malaria, could increase the effectiveness of the most common current treatments for GBM.
 
An initial study published in Oncotarget* indicated that HSPs contribute to development of GBM and radio/TMZ resistant GBM through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT). The recent discovery published in Proceedings of the National Academy of Sciences of the United States of America further indicates that Fli-1, which transcriptionally regulates HSPB1 and is linked to oncogenic transformation, is upregulated in radio/TMZ resistant GBM. Based on the potential relationship between Fli-1 expression and radio/TMZ resistance in GBM cells, a screening approach for Fli-1 inhibitors was performed which identified an FDA-approved drug, lumefantrine (Figure 1-left), as a potential therapeutic agent in GBM treatment. These studies confirm that targeted inhibition of Fli-1/HSPB1-mediated EMT and ECM remodeling signaling axes (Figure 1-right) by lumefantrine provides a novel therapeutic reagent for radio/TMZ-resistance in GBM. Fli-1 overexpression has been established as a biomarker in several other cancers, which opens up the new directions for investigating this target and targeted therapies in other cancers as well.
Dr. Yetirajam Rajesh, a postdoctoral research scientist in Human and Molecular Genetics at Virginia Commonwealth University, School of Medicine is the lead author of this paper, and performed much of the biological and animal work. The present study was supported in part by Department of Science and Technology-INSPIRE (IF130658), Indian Institute of Technology Kharagpur and Ministry of Human Resource Development, India. SERB, New Delhi, India- JCB/2019/000008, Indian Council of Medical Research: 5/13/7/2019- NCD-III and Council of Scientific & Industrial Research, New Delhi, India - 27(0347)/19/EMR-II. Genetics Enhancement Fund of the Department of Human and Molecular Genetics and the VCU Institute of Molecular Medicine (to P.B. Fisher) and the Genetics Enhancement Fund (to P.B. Fisher, S.K. Das, and L. Emdad).
 
Publications:
* Rajesh Y, Biswas A, Banik P, Pal I, Das S, Borkar SA, Sardana H, Saha A, Das SK, Emdad L, Fisher PB, Mandal M. Transcriptional Regulation of HSPB1 by Friend Leukemia integration-1 Factor Modulates Radiation and Temozolomide Resistance in Glioblastoma. Oncotarget 2020 Mar 31;11(13):1097-1108. PMCID: PMC7138161
** Rajesh Y, Biswas A, Kumar U, Banerjee I, Das S, Maji S, Das SK, Emdad L, Cavenee WK, Mandal M, Fisher PB. Lumefantrine, an Antimalarial Drug, Reverses Radiation and Temozolomide Resistance in Glioblastoma.Proc Natl Acad Sci U S A. 2020 Jun 2;117(22):12324-12331. PMCID: PMC7275698
 
About the Investigators: Paul B. Fisher, MPh, PhD, FNAI, is Professor and Chair of Human and Molecular Genetics (HMG), Director of the VCU Institute of Molecular Medicine (VIMM) and Thelma Newmeyer Corman Chair in Cancer Research in the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Yetirajam Rajesh, PhD, is the first author of this research study, and along with Santanu Maji, PhD are postdoctoral research scientists in HMG. Swadesh K. Das, PhD, and Luni Emdad, MBBS, PhD are Associate Professors in HMG and Members of the VIMM. Angana Biswas, Payel Banik, Ipsita Pal, Sachin A. Borkar, Hardik Sardana, Abhijit Saha, Utkarsh Kumar, Indranil Banerjee, Subhayan Das and Mahitosh Mandal are from Indian Institute of Technology Kharagpur, India. Webster K. Cavenee is from Ludwig Institute for Cancer Research, UCSD, San Diego, CA, USA.