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Repurposing mebendazole against triple-negative breast cancer leptomeningeal disease.
Rodrigues, Adrian; Chernikova, Sophia B; Wang, Yuelong; Trinh, Thy T H; Solow-Cordero, David E; Alexandrova, Ludmila; Casey, Kerriann M; Alli, Elizabeth; Aggarwal, Abhishek; Quill, Tyler; Koegel, Ashley; Feldman, Brian J; Ford, James M; Hayden-Gephart, Melanie.
Afiliación
  • Rodrigues A; Massachusetts General Hospital.
  • Chernikova SB; Stanford University.
  • Wang Y; Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China.
  • Trinh TTH; Department of Neurosurgery, Stanford School of Medicine, Stanford, CA 94305.
  • Solow-Cordero DE; High-Throughput Screening Knowledge Center, Sarafan ChEM-H, Stanford CA 94305.
  • Alexandrova L; Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA, 94305.
  • Casey KM; Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305.
  • Alli E; Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27109.
  • Aggarwal A; High-Throughput Screening Knowledge Center, Sarafan ChEM-H, Stanford CA 94305.
  • Quill T; Department of Materials Science and Engineering, Stanford University, Stanford, CA 94305.
  • Koegel A; Department of Pediatric Hematology-Oncology, University of California, San Francisco, CA 94143.
  • Feldman BJ; Department of Pediatrics, University of California, San Francisco, CA 94143.
  • Ford JM; Department of Medicine (Oncology), Stanford School of Medicine, Stanford, CA 94305.
  • Hayden-Gephart M; Department of Neurosurgery, Stanford School of Medicine, Stanford, CA 94305.
Res Sq ; 2024 Feb 05.
Article en En | MEDLINE | ID: mdl-38405839
ABSTRACT

Purpose:

Triple-negative breast cancer (TNBC) is an aggressive subtype that often metastasizes to the brain. Leptomeningeal disease (LMD), a devastating brain metastasis common in TNBC, has limited treatment options. We sought to test whether the common anti-helminthic drug mebendazole (MBZ) may be effective against murine TNBC LMD.

Methods:

A small-molecule screen involving TNBC cell lines identified benzimidazoles as potential therapeutic agents for further study. In vitro migration assays were used to evaluate cell migration capacity and the effect of MBZ. For in vivo testing, LMD was introduced into BALB/c athymic nude mice through internal carotid artery injections of brain-tropic MDA-MB-231-BR or MCF7-BR cells. Tumor growth and spread was monitored by bioluminescence imaging. MBZ was given orally at 50 and 100 mg/kg doses. MBZ bioavailability was assayed by mass spectrometry.

Results:

Bioinformatic analysis and migration assays revealed higher migratory capacity of TNBC compared to other breast cancer subtypes. MBZ effectively slowed down migration of TNBC cell line MDA-MB-231 and its brain tropic derivative MDA-MB-231-BR. In animal studies, MBZ reduced tumor growth and extended survival in the LMD model produced by MDA-MB-231-BR cells. MBZ did not have an effect in the non-migratory MCF7-BR model.

Conclusions:

We demonstrated that MBZ is a safe and effective oral agent in an animal model of TNBC LMD. Our findings are concordant with previous efforts involving MBZ and central nervous system pathology and further support the drug's potential utility as an alternative therapeutic for TNBC LMD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Sq Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Res Sq Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos