Methods of downregulating translocated oncogene expression using bromodomain inhibitors
AssigneesDana-Farber Cancer Institute, Inc., Whitehead Institute for Biomedical Research
InventorsRichard A. Young, Peter B. Rahl, James Bradner
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Abstract
Disclosed herein are novel methods and compositions useful for inhibiting interaction between a bromodomain protein and an immunoglobulin (Ig) regulatory element. The methods and compositions are particularly useful for downregulating expression of an oncogene translocated with an Ig locus, as well as for treating a cancer (e.g., hematological malignancy) characterized by increased expression of an oncogene which is translocated with an Ig locus. Also disclosed herein are methods and assays for identifying agents that interfere with binding of bromodomain proteins to Ig regulatory elements, as well as methods and assays for identifying inhibitors of bromodomain
Claims37
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A method for downregulating expression of an oncogene translocated with an Ig locus comprising contacting said locus with an effective amount of an inhibitor of a bromodomain protein.
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A method for treating a cancer comprising:
- (a) determining the level of expression of an oncogene translocated with an Ig locus in a sample obtained from an individual having or suspected of having said cancer, wherein overexpression of said translocated oncogene in said sample in comparison with a control is indicative that said individual is an individual who would potentially benefit from treatment with an inhibitor of a bromodomain protein;
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- (b) administering an effective amount of said inhibitor to said individual if said translocated oncogene is overexpressed in said sample.
A method for treating a cancer comprising administering an effective amount of an inhibitor of a bromodomain protein to an individual exhibiting overexpression of an oncogene translocated with an Ig locus.
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A method for identifying an agent that interferes with binding of a bromodomain protein to an Ig regulatory element comprising:
- (a) contacting a suitably conditioned cell containing a target gene under control of one or more Ig regulatory elements and a bromodomain protein which binds to said one or more Ig regulatory elements and activates expression of said target gene with a candidate agent;
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- (b) detecting expression of said target gene, wherein decreased expression of said target gene in the presence of said candidate agent as compared with expression of said target gene in the absence of said candidate agent is indicative of said agent's ability to interfere with binding of said bromodomain protein to said Ig regulatory element.
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A method for identifying an inhibitor of a bromodomain protein comprising:
- (a) contacting a cell line expressing an oncogene translocated with an Ig locus with a candidate agent;
- (b) measuring the level of bromodomain protein occupancy at a regulatory element of said Ig locus;
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- (c) comparing said level of bromodomain occupancy at said regulatory element of said Ig locus to a control, wherein decreased bromodomain protein occupancy at said regulatory element of said Ig locus in the presence of the candidate agent as compared to in the absence of said candidate agent is indicative of bromodomain inhibitory activity of said candidate agent.
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Dependencies are inferred from the claim text.