Laboratory Investigation

Journal of Neuro-Oncology

, Volume 79, Issue 3, pp 259-270

First online:

Suberoylanilide hydroxamic acid is effective in preclinical studies of medulloblastoma

  • Susan E. SpillerAffiliated withFred Hutchinson Cancer Research CenterDepartment of Pediatrics, University of Washington and Children’s Hospital and Regional Medical Center
  • , Ali C. RavanpayAffiliated withFred Hutchinson Cancer Research CenterProgram in Neurobiology and Behavior, University of Washington
  • , Andrew W. HahnAffiliated withFred Hutchinson Cancer Research Center
  • , James M. OlsonAffiliated withFred Hutchinson Cancer Research CenterDepartment of Pediatrics, University of Washington and Children’s Hospital and Regional Medical Center Email author 

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Abstract

Purpose

Suberoylanilide hydroxamic acid (SAHA) has been studied in adult solid and hematologic malignancies. However, little information has been reported on the effects of SAHA on central nervous system (CNS) tumors including medulloblastoma, the most common malignant brain tumor in children. We investigated SAHA in preclinical medulloblastoma models to determine its anti-cancer efficacy as well as its ability to␣affect intracranial lesions when administered systemically.

Experimental design and results

Tissue culture studies were performed treating primary human fibroblasts, established medulloblastoma cell lines, and primary human medulloblastoma tumors with SAHA. At 10 µM concentration, SAHA had little effect on normal fibroblasts but caused >90% apoptosis in cultured medulloblastoma cells. Primary medulloblastomas from patients were sensitive to SAHA compared to vehicle alone in ex vivo studies. In athymic mice with medulloblastoma xenograft tumors, oral SAHA resulted in apoptosis of tumor tissue and significantly slowed tumor growth. In the ND2:Smo transgenic mouse medulloblastoma model, SAHA treatment caused significant apoptosis in these cerebellar tumors.

Conclusions

SAHA effectively induces cell death in established medulloblastoma cell lines, human patient primary tumor cultures, medulloblastoma xenografts and intracranial spontaneous medulloblastomas. Fibroblasts in culture and mice treated with SAHA did not reveal prohibitive toxicity profiles. These findings support the advancement of SAHA to pediatric clinical trials.

Keywords

HDI Brain tumor Pediatric Medulloblastoma SAHA ND2:Smo