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Targeting BET Bromodomains in Cancer –
Mechanisms of Sensitivity and Resistance

Obiettivo

Besides DNA mutations, cancers harbor complex aberrations of the epigenetic landscape, which are reversible and amenable to pharmacologic intervention. Therapeutic targeting of chromatin regulators has shown great promise in first clinical studies, and this has triggered a massive effort to explore this machinery in academic and pharmaceutical research. Recently, the bromodomain and extraterminal domain (BET) containing protein 4 (BRD4), a reader of histone-acetyl marks, has emerged as a promising therapeutic target, and newly identified small-molecule BET inhibitors have shown impressive effects in preclinical cancer models. Unlike most established drug targets, BRD4 is typically not mutated or overexpressed in sensitive cell types, yet different cancer contexts show vast differences in their sensitivity to BET inhibition. This suggests that cancer cells can become “non-oncogene addicted” to BRD4. However, the mechanistic basis for this phenomenon remains elusive and so far no biomarker could be identified for predicting the sensitivity or resistance to BET inhibition. Moreover, preliminary results in an AML mouse model suggest that cells can rapidly become resistant to BRD4 inhibition, most likely through an epigenetic mechanism. This project will use an innovative approach combining proteomic profiling, advanced RNAi technologies and experimentally tractable mouse models of cancer to systematically identify and functionally characterize molecular determinants of sensitivity and resistance to BET inhibition. Advancing this mechanistic understanding will not only be critical for the further development of BET inhibitors in the clinic, but may reveal other key players that might be interesting as complementary or alternative target molecules. We believe that this study will contribute to a better understanding of epigenetic mechanisms in cancer and therapy resistance, which will be essential for further exploring this promising class of therapeutic targets.
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Coordinatore

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH

Indirizzo

Campus-Vienna-Biocenter 1
1030 Wien

Austria

Tipo di attività

Private for-profit entities (excluding Higher or Secondary Education Establishments)

Contributo UE

€ 186 783,60

Contatto amministrativo

Tanja Winkler (Mrs.)

Informazioni relative al progetto

ID dell’accordo di sovvenzione: 329492

Stato

Progetto concluso

  • Data di avvio

    1 Marzo 2013

  • Data di completamento

    28 Febbraio 2015

Finanziato da:

FP7-PEOPLE

  • Bilancio complessivo:

    € 186 783,60

  • Contributo UE

    € 186 783,60

Coordinato da:

FORSCHUNGSINSTITUT FUR MOLEKULARE PATHOLOGIE GESELLSCHAFT MBH

Austria

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