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

Author:

Hwang Grace H.12ORCID,Pazyra-Murphy Maria F.12ORCID,Seo Hyuk-Soo13ORCID,Dhe-Paganon Sirano13ORCID,Stopka Sylwia A.4ORCID,DiPiazza Marina4ORCID,Sutter Nizhoni45ORCID,Gero Thomas W.1ORCID,Volkert Alison1ORCID,Ombelets Lincoln1ORCID,Dittemore Georgia1ORCID,Rees Matthew G.6ORCID,Ronan Melissa M.6ORCID,Roth Jennifer A.6ORCID,Agar Nathalie Y.R.147ORCID,Scott David A.13ORCID,Segal Rosalind A.12ORCID

Affiliation:

1. 1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.

2. 2Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.

3. 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.

4. 4Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

5. 5Brigham Young University-Hawaii, Kulanui St, Hawaii.

6. 6Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

7. 7Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Abstract

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.

Funder

Alex's Lemonade Stand Foundation for Childhood Cancer

Helen Gurley Brown Foundation

National Cancer Institute

National Institutes of Health

Publisher

American Association for Cancer Research (AACR)

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