A Benzarone Derivative Inhibits EYA to Suppress Tumor Growth in SHH Medulloblastoma

  • Cancer Res. 2024 Mar 15;84(6):872-886. doi: 10.1158/0008-5472.CAN-22-3784.
Grace H Hwang  1  2 ,  Maria F Pazyra-Murphy  1  2 ,  Hyuk-Soo Seo  1  3 ,  Sirano Dhe-Paganon  1  3 ,  Sylwia A Stopka  4 ,  Marina DiPiazza  4 ,  Nizhoni Sutter  4  5 ,  Thomas W Gero  1 ,  Alison Volkert  1 ,  Lincoln Ombelets  1 ,  Georgia Dittemore  1 ,  Matthew G Rees  6 ,  Melissa M Ronan  6 ,  Jennifer A Roth  6 ,  Nathalie Y R Agar  1  4  7 ,  David A Scott  1  3 ,  Rosalind A Segal  1  2
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 2. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.
  • 3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
  • 4. Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 5. Brigham Young University-Hawaii, Kulanui St, Hawaii.
  • 6. Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 7. Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
PMID: 38486486 DOI: 10.1158/0008-5472.CAN-22-3784
Abstract

Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase Phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1-38 functioned as an EYA antagonist and opposed SHH signaling. DS-1-38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising therapies for pediatric SHH-MB.

Significance: Development of a benzarone derivative that inhibits EYA1 and impedes the growth of SHH medulloblastoma provides an avenue for improving treatment of this malignant pediatric brain Cancer.

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