Diagnostic methylation markers of epithelial or mesenchymal phenotype and response to EGFR kinase inhibitor in tumours or tumour cells

A tumor cell, methylation technology, applied in the field of diagnostic methylation markers of epithelial or mesenchymal phenotype and response to EGFR kinase inhibitors in tumor or tumor cells, can address the reduction of vulnerability And other issues

Inactive Publication Date: 2014-09-24
GENENTECH INC
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  • Abstract
  • Description
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Problems solved by technology

Additionally, this can result in reduced vulnerability to transition mutations, thus resulting in the persistence of a higher equilibrium density of CpG

Method used

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  • Diagnostic methylation markers of epithelial or mesenchymal phenotype and response to EGFR kinase inhibitor in tumours or tumour cells
  • Diagnostic methylation markers of epithelial or mesenchymal phenotype and response to EGFR kinase inhibitor in tumours or tumour cells
  • Diagnostic methylation markers of epithelial or mesenchymal phenotype and response to EGFR kinase inhibitor in tumours or tumour cells

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Experimental program
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preparation example Construction

[0142]In the preparation of compositions for oral dosage form, any convenient pharmaceutical vehicle may be employed. For example, water, glycols, oils, alcohols, flavor enhancers, preservatives, coloring agents, etc. can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, Diluents, granulating agents, lubricants, binding agents, disintegrating agents and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or non-aqueous techniques.

[0143] A tablet containing a composition for use in the present invention may be made by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be pre...

Embodiment 1

[0237] Example 1 - Materials and methods

[0238] Fluidigm expression analysis : EMT gene expression analysis was performed on 82 NSCLC cell lines using the BioMark96 × 96 gene expression platform (Fluidigm) and the 20-gene EMT expression set (Supplementary Table S1 and Methods). ΔCt values ​​were used to cluster cell lines according to EMT gene expression levels using Cluster v.3.0 and Treeview v.1.60 software.

[0239] Illumina Infinium Analysis : Microarray data were collected at Expression Analysis, Inc. (Durham, N.C.) using the Illumina Human Methylation 450 BeadChip (Illumina, San Diego, CA) as described below. Array data were analyzed and a methylation classifier was built using a "leave-one-out" cross-validation strategy (described below and in refs 25, 26). Array data have been submitted to the Gene Expression Omnibus database (accession number GSE36216).

[0240] cell line : All NSCLC cell lines were purchased from the American Type Culture Collection (ATCC) ...

Embodiment 2

[0258] Example 2 - Epithelial-like and mesenchymal-like expression signatures correlate with erlotinib sensitivity in vitro

[0259] A gene expression signature associated with in vitro sensitivity of NSCLC cell lines to erlotinib was previously defined (11). This gene set is highly enriched for genes involved in EMT. developed a quantitative reverse transcriptase PCR-based EMT expression set on the Fluidigm nanofluidic platform ( figure 1 ). A comparison of the 100-probe set from Yauch et al.'s study (11) with the 20-gene EMT Fluidigm set of 42 strains profiled in Yauch et al.'s study showed that this 20-gene expression set is a representative classifier for EMT (ref. 11 ).

[0260] To further assess whether the 20-gene set is representative of the phenotypic changes associated with EMT, 2 cell lines were treated with TGFβ1. The results of this study showed that TGFβ1 induces morphological changes associated with EMT. In these cell lines, genes associated with the epithe...

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Abstract

The present invention provides methods for determining epithelial and mesenchymal phenotype of tumors and predicting whether tumor growth will be sensitive or resistant to treatment with an EGFR inhibitor. In particular, presence or absence of methylation of DNA at a CpG site in at least one gene selected from the group consisting of CLDN7, HOXC4, CP2L3, TBCD, ESPR1, GRHL2, ERBB2, and C20orf55 is provided as a marker of a mesenchymal phenotype in a tumour cell, for determining the sensitivity of tumor growth to inhibition by an EGFR kinase inhibitor, and / or for identifying a cancer patient who is likely to benefit from treatment with an EFGR inhibitor. Presence or absence of methylation of DNA at a CpG site in at least one gene selected from the group consisting of the PCDH8, PEX5L, GALR1, and ZEB2 is provided as a marker of epithelial phenotype of a tumor cell.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 61 / 542,141 filed September 30, 2011, the disclosure of which is hereby incorporated by reference in its entirety. field of invention [0003] The present invention provides methods for predicting response to cancer therapy based on the methylation status of a gene. Background of the invention [0004] The present invention is directed to methods for diagnosing and treating cancer patients. In particular, the invention is directed to methods for determining which patients would benefit most from treatment with an epidermal growth factor receptor (EGFR) kinase inhibitor. [0005] Cancer is the general name for a wide range of cellular malignancies characterized by unregulated growth, lack of differentiation, and the ability to invade local tissues and metastasize. These neoplastic malignancies affect every tissue and organ in the body in varying degr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCC12Q1/6886C12Q2600/112C12Q2600/106C12Q1/6827C12Q2600/154A61P35/00
Inventor D.夏姆斯T.M.霍尔科姆K.沃尔特
Owner GENENTECH INC
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