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Biomarkers for response to ezh2 inhibitors

A biomarker and inhibitor technology, applied in the field of biomarkers for response to EZH2 inhibitors, can solve problems such as poor prognosis and no confirmed effective treatment

Active Publication Date: 2017-05-31
MEMORIAL SLOAN KETTERING CANCER CENT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Some patients with BAP1 mutations have a rather poor prognosis with no confirmed effective treatment, while many patients with malignant mesothelioma will succumb to their disease

Method used

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  • Biomarkers for response to ezh2 inhibitors
  • Biomarkers for response to ezh2 inhibitors
  • Biomarkers for response to ezh2 inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] 6. Example 1: Deletion of BAP1 in vitro leads to increased expression and activity of EZH2

[0128] In this example, the mechanism by which loss of BAP1 activity leads to a disease state is studied in vitro.

[0129] 6.1. Results

[0130] SET2 cells were transduced with shRNA targeting BAP1 to reduce BAP1 expression in vitro. As verified by Western blot, reduction of BAP1 expression resulted in increased trimethylation (H3K27me3) of histone 3 at K27 ( figure 1 ). See also Figure 9A. BAP1 protein expression was depleted in BaF3 cells, while BAP1 loss was confirmed by western blot and histone profiling was performed. BAP1 knockdown in BaF3 cells showed increased H3K27me3 ( figure 1 ).

[0131] BAP1 has been shown to be highly mutated in solid tumors such as malignant mesothelioma and uveal melanoma (Carbone et al., 2012). Upregulation of EZH2 expression was observed in mesothelioma cells with mutations in BAP1 such as H28 homozygous deletion, H2452 homozygous mis...

Embodiment 2

[0134] 7. Example 2: Deletion of BAP1 in vivo leads to increased expression and activity of EZH2

[0135] 7.1 Methods and materials

[0136] Primers:

[0137] Table 1

[0138]

[0139]

[0140] Animals: All animals were obtained from Memorial Sloan Kettering Cancer Center. All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee of Memorial Sloan Kettering Cancer Center.

[0141] Generation of Bap1-deficient and Bap1 / Ezh2-deficient mice:

[0142] Embryonic stem cells targeting exons 6-12 of Bapl were obtained from the European Conditional Mouse Consortium. An Frt-flanking premature termination cassette containing the lacZ and neomycin cassettes was inserted upstream. ES cell clones were expanded and injected into primary blastocysts. The resulting mice were crossed to a Flp-deleted sub-line (The Jackson Laboratory) to excise the Frt-flanked casse...

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Abstract

The presently disclosed subject matter relates to the use of one or more biomarkers to evaluate the likelihood that an EZH2 inhibitor would produce an anticancer effect in a subject. It is based, at least in part, on the discovery that loss of BAPl results in the upregulation of EZH2 expression and activity. In a specific non-limiting embodiment, the method comprises obtaining a sample of the cancer from a subject, and determining, in the sample, the expression level of an BAPl biomarker, where if the BAP 1 biomarker is absent or expressed at lower level in the cancer as compared to a reference control level, then administering a therapeutically effective amount of an EZH2 inhibitor to produce an anti-cancer effect.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application Serial No. 62 / 014,594, filed June 19, 2014, the entire contents of which are incorporated herein by reference. [0003] grant information [0004] This invention was made with government support under Grant Number F31CA180642-01 awarded by the National Institutes of Health. The government has certain rights in this invention. [0005] 1. Technical field [0006] The present invention relates to biomarkers useful for assessing the likelihood of an EZH2 inhibitor producing an anticancer effect in a subject. Accordingly, these biomarkers can be used in methods of treating cancer patients. [0007] 2. Background technology [0008] BRCA1-associated protein-1 (BAP1) is an ubiquitin carboxy-terminal hydrolase involved in the removal of ubiquitin from proteins. BAP1 binds BRCA1 through the RING finger domain of breast cancer type 1 susceptibility prote...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68G01N33/68G01N33/574
CPCG01N33/5011G01N2333/91017G01N2800/7028C12Q1/6886C12Q2600/106C12Q2600/158A61K31/5377C12Q1/68G01N33/5748G01N2333/948
Inventor R·莱维纳L·拉费O·阿卜杜勒-瓦哈卜
Owner MEMORIAL SLOAN KETTERING CANCER CENT
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