Preclinical rationale for entinostat in embryonal rhabdomyosarcoma

Bharathy, N., Berlow, N. E., Wang, E., Abraham, J., Settelmeyer, T. P., Hooper, J. E., Svalina, M. N., Bajwa, Z., Goros, M. W., Hernandez, B. S., Wolff, J. E., Pal, R., Davies, A. M., Ashok, A., Bushby, D., Mancini, M., Noakes, C., Goodwin, N. C., Ordentlich, P., Keck, J., Hawkins, D. S., Rudzinski, E. R., Mansoor, A., Perkins, T. J., Vakoc, C. R., Michalek, J. E., Keller, C. (May 2019) Preclinical rationale for entinostat in embryonal rhabdomyosarcoma. Skelet Muscle, 9 (1). p. 12. ISSN 2044-5040

[img]
Preview
PDF
2019.Bharathy.Vakoc.Rhabdomyosarcoma.pdf - Published Version

Download (3545Kb) | Preview
URL: https://www.ncbi.nlm.nih.gov/pubmed/31113472
DOI: 10.1186/s13395-019-0198-x

Abstract

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). METHODS: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. RESULTS: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusion-negative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. CONCLUSION: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > histone deacetylase
diseases & disorders > cancer > cancer types > sarcoma
CSHL Authors:
Communities: CSHL labs > Vakoc lab
Depositing User: Matthew Dunn
Date: 21 May 2019
Date Deposited: 29 May 2019 19:42
Last Modified: 29 May 2019 19:42
Related URLs:
URI: http://repository.cshl.edu/id/eprint/37994

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving