Econazole selectively induces cell death in NF1-homozygous mutant tumor cells

Yenal B Lakes; Stefanie L Moye; Juan Mo; Matthew Tegtmeyer; Ralda Nehme; Maura Charlton; Gabrielle Salinas; Renee M McKay; Kevin Eggan; Lu Q Le

doi:10.1016/j.xcrm.2023.101309

Econazole selectively induces cell death in NF1-homozygous mutant tumor cells

Cell Rep Med. 2023 Dec 19;4(12):101309. doi: 10.1016/j.xcrm.2023.101309. Epub 2023 Dec 11.

Authors

Affiliations

¹ Department of Stem Cell and Regenerative Medicine, Harvard University, Boston, MA, USA.
² Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Medical Scientist Training Program, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
⁵ Department of Stem Cell and Regenerative Medicine, Harvard University, Boston, MA, USA. Electronic address: [email protected].
⁶ Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; O'Donnell Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: [email protected].

Abstract

Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1^+/- and NF1^-/- hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1^-/- but not NF1^+/- cell proliferation. We identify econazole nitrate as being effective against NF1^-/- hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1^-/- murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.

Keywords: NF1; Schwann cell precursors; cutaneous neurofibroma; econazole; human induced pluripotent stem cells; neurofibromatosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Econazole
Humans
Induced Pluripotent Stem Cells* / metabolism
Mice
Neurofibroma* / genetics
Neurofibroma* / metabolism
Neurofibroma* / pathology
Neurofibromatosis 1* / drug therapy
Neurofibromatosis 1* / genetics
Neurofibromatosis 1* / metabolism
Skin Neoplasms* / drug therapy
Skin Neoplasms* / genetics
Skin Neoplasms* / metabolism
United States

Substances

Econazole