Compositions and methods for selecting a treatment for b-cell neoplasias

a b-cell neoplasia and treatment technology, applied in the field of b-cell neoplasia treatment selection, can solve the problems of treatment resistance often developing, and achieve the effects of reducing the proliferation of a cell, increasing the expression of ikzf1 or ikzf3, and reducing the expression of ikzf1 or ikzf3

Inactive Publication Date: 2016-09-29
THE BRIGHAM & WOMEN S HOSPITAL INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0011]In still another aspect, the invention provides a method of reducing the proliferation of a cell characterized by increased IKZF1 or IKZF3 polypeptide expression, the method involving contacting the cell with an inhibitory nucleic acid molecule that reduces the ex...

Problems solved by technology

However, for most multiple myeloma patients, the disease eventually...

Method used

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  • Compositions and methods for selecting a treatment for b-cell neoplasias
  • Compositions and methods for selecting a treatment for b-cell neoplasias
  • Compositions and methods for selecting a treatment for b-cell neoplasias

Examples

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example 1

DNA Damage Binding Protein 1 (DDB1) and Carbonyl Reductase 1 (CBR1) Bind to Lenolidomide

[0169]Lenalidomide is a highly effective drug for the treatment of multiple myeloma (Rajkumar et al., Blood 106, 4050 (Dec. 15, 2005).) and del(5q) MDS (List et al., N Engl J Med 352, 549 (Feb. 10, 2005)), and its use in a range of other conditions is being actively explored, but the precise mechanism of action of lenalidomide has not been established. In addition, lenalidomide and its analogues thalidomide and pomalidomide have multiple additional biological effects, including stimulation of IL-2 production by T cells, and inhibition of TNF production by monocytes, but the molecular basis of these pleiotropic activities is unknown.

[0170]In order to identify direct protein targets of lenalidomide, a derivative of lenalidomide was synthesized that allowed immobilization of the molecule to a bead (FIG. 2A). This derivative retained the biological activity of lenalidomide, including selective growth...

example 2

Lenalidomide Regulates Ikaros (IKZF1) and Aiolos (IKZF3)

[0173]Two proteins, Ikaros (IKZF1) and Aiolos (IKZF3), scored at the top of the lists of proteins regulated by lenalidomide at both the protein and ubiquitin-site level (FIG. 1C, 1D). Lenalidomide decreased the abundance of IKZF3 (log2 ratio −2.09) and IKZF1 (log2 ratio −1.54). While increased ubiquitination would be expected to be associated with decreased protein abundance, a decrease in ubiquitination of multiple lysine residues of IKZF1 and IKZF3 was observed after treating cells with lenalidomide for 12 hours prior to addition of the proteasome inhibitor MG132. A likely interpretation of these results is that IKZF1 and IKZF3 are rapidly ubiquitinated, targeting them for degradation and thereby resulting in a decrease in abundance of both ubiquitinated and absolute levels of these proteins. IKZF1 and IKZF3 also scored at the top of the list of thalidomide-regulated proteins, consistent with the similar biological activity o...

example 3

Lenalidomide Induced Ubiquitination of IKZF1 and IKZF3

[0177]The direct effect of lenalidomide on ubiquitination of IKZF1 and IKZF3 was assessed. Lenalidomide induced dose-dependent ubiquitination of tagged IKZF1 and IKZF3 in MM1S and 293′ cells (FIG. 8A-8C). Cain-RING ubiquitin ligase (CRL) activity depends on NEDDylation and can be inhibited by the Nedd8 enzyme inhibitor MLN4924. Treatment with 1 μM MLN-4924 prevented the lenalidomide-induced decrease of endogenous IKZF1 and IKZF3 in MM1S cells and of FFluc-fused IKZF3 in 293T cells. These experiments demonstrate that lenalidomide-induced degradation of IKZF1 and IKZF3 involves ubiquitination by a cullin-based E3 ubiquitin ligase.

[0178]Experiments were carried out to determine whether lenalidomide-induced ubiquitination of IKZF1 and IKZF3 is caused by altered binding of these proteins to CRBN, as observed in our proteomic studies. These experiments confirmed that more IKZF1 and IKZF3 co-irnmunoprecipitate with HA-CRBN after 3 hours...

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Abstract

The present invention features compositions and methods for identifying a subject having a B cell neoplasia or related condition responsive to treatment with lenalidomide and lenalidoinide-related compounds.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of and priority to U.S. Provisional Application Ser. No. 61 / 902,066, filed Nov. 8, 2013, and U.S. Provisional Application Ser. No. 61 / 915,439, filed Dec. 12, 2013, the contents of which are incorporated herein by reference.STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH[0002]This work was supported by the following grants from the National Institutes of Health, Grant Nos: R01HL082945 and P01 CA108631. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]B lymphocytes are an important cellular component of the adaptive immune system. When normal B-cell development goes awry, B-cell neoplasia can result. B cell neoplasms include multiple myeloma, mantle cell lymphoma and chronic lymphocytic leukemia. Multiple myeloma is a malignant plasma cell disorder and is the second most common hematologic malignancy in the United States, with about 20 000 patie...

Claims

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Application Information

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IPC IPC(8): G01N33/574G01N33/94G01N33/50
CPCG01N33/57496G01N33/5088G01N2333/47G01N33/5011G01N33/94C12Q1/6886C12Q2600/106C12Q2600/156C12Q2600/158A01K67/0278A01K2217/072A01K2227/105A01K2267/03C12Q1/6876C12Q2600/136
Inventor EBERT, BENJAMIN LEVINECARR, STEVEN A.KRONKE, JANUDESHI, NAMRATA D.FINK, EMMA
Owner THE BRIGHAM & WOMEN S HOSPITAL INC
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