ECTS2013 Poster Presentations Cancer and bone: basic, translational and clinical (31 abstracts)
Selective BET bromodomains epigenetic signaling inhibition as a therapeutic strategy in primary bone tumors
Francois Lamoureux 1, , Marc Baud’huin 1, , Lidia Rodriguez 1, , Camille Jacques 1, , Martine Berreur 1, , James E Bradner 3, , Francoise Redini 1, , Dominique Heymann 1, & Benjamin Ory 1,
1INSERM, UMR-S 957, 1 Rue Gaston Veil, Nantes, France; 2Physiopathologie de la Résorption Osseuse et Thérapie des Tumeurs Osseuses Primitives, Université de Nantes, Nantes Atlantique Universités, EA3822, Nantes, France; 3Department of Medical Oncology, Harvard Medical School, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts, USA; 4Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts, USA.
Osteosarcoma is the most frequent primary bone tumor that develops mainly in young adults. The survival rate at 5 years is below 30% for patients with poor response to treatment or with metastasis.
The histones modifications are of critical importance in maintaining the transcription program of both normal and tumor cells. The bromodomain and extra-terminal domain (BET) protein family is an important class of ‘histone reading protein’ capable to recognize the N-acetylation of lysine residues on histone tails. BET bromain proteins have recently been described as regulators of MYC expression in various tumors. In this study, we present the therapeutic opportunity to pharmacologically target the BET bromodomain family in primary bone tumors.
The consequence of this pharmacologic inhibition of bromodomains is a wide gene expression alteration, but it is believed to selectively target malignant cells by disrupting transcription at intense activity, most notably MYC and Runx2 in our model. Considering MYC and Runx2 are of particular importance for the oncogenic potential of primary bone tumors, a therapeutic strategy targeting those networks might be extremely relevant and potent.
In osteosarcoma tumor cell lines, BET inhibitor reduced cell growth in a dose-dependent manner and induced apoptosis with an increase of sub-G1 fraction and PARP cleavage. These biological events were accompanied by decreased expression and activity of both MYC and Runx-2, and by an expression modulation of their target genes. Moreover, BET inhibitor affects bone remodeling process by disrupting both osteoclast and osteoblast differenciation. In vivo, BET inhibitor (i.p.; 50 mg/kg) significantly inhibits tumor growth by 70% and prolongs survival in both POS-1 syngenic and HOS xenograft models compared to control. Additionnally, these results were accompanied by a decrease of associated bone lesions.
These findings demonstrate that dual pharmacologic inhibition of MYC and Runx-2 is achievable through targeting BET bromodomains to treat osteosarcoma.
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Bone Abstracts
ISSN 2052-1219 (online)
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