Cancer genome and non-specific gene tag-based large-scale drug relocation method

A gene and labeling technology, applied in the field of large-scale drug repositioning, can solve problems such as inability to be used in clinical treatment, interference of expression profile tags, and inability to implement in humans

Active Publication Date: 2018-10-16
SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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Problems solved by technology

Third, the current drug development is mostly based on cell in vitro screening and model animal testing, but in the end most of them are ineffective on humans or have strong side effects and cannot be used for clinical treatment
1. To mine the expression profile tags of genome-wide genes from the existing database will face problems such as inconsistency in data platforms and differences in data batches, making it impossible to perform unified quantitative analysis
Second, a small number of existing open data for unified analysis and processing do not cover all gene targets. For example, The Encyclopedia of DNA Elements (ENCODE) database only contains 430 transcription factors, which is too narrow compared to the approximately 25,000 genes in the human genome
Third, most of the existing data used to analyze gene expression profiles come from genetic experiment data. However, these experiments can only be carried out on cell lines or model animals, and cannot be implemented in humans. Therefore, the

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specific Embodiment approach

[0065] As a specific embodiment of the present invention, the data is obtained from the Connectivity Map (CMap) database, preferably, the drug treatment expression profile tags are analyzed from the microarray chip of the CMap database, so as to be integrated with the core tags for analysis.

[0066] In a specific embodiment of the present invention, based on the drug repositioning method of the present invention, the core tags determined by the method of the present invention are compared with 3,546 sets of drug processing data, and 5,362,359 drug repositioning candidate results are determined, including 2,511,089 drug-gene interaction relationships predicted for unknown target drugs were obtained.

[0067] In the method of the present invention, after obtaining the drug repositioning candidate results, it also includes: performing further cell experiment / animal experiment verification on the function (potential therapeutic effect) determined after drug repositioning, so as to...

Embodiment 1

[0073] Example 1. Construction of core tags of key signaling pathway genes from cancer transcriptome

[0074] In order to construct the core tags of key signaling pathways, in this example, 4,895 key signaling pathway genes responsible for encoding receptors, signaling cascade factors and transcription factors were collected.

[0075] The TCGA database provides thousands of sets of high-quality transcriptome data for more than 20 cancer types, as well as tissue-type-matched normal control data. In this embodiment, the TCGA database is used as the basis for determining the core tags.

[0076] Based on the TCGA database, the inventor has designed 5 steps to realize the construction of core tags ( figure 1 ). For each cancer type, the patient sample group carrying a mutation type of a gene (missense mutation, nonsense mutation, frameshift mutation deletion or insertion, etc.) Control group comparison to find the expression profile signature of the gene in different mutation ty...

Embodiment 2

[0083] Example 2. Drug relocation based on gene core tags and drug processing transcriptome data

[0084] In order to apply the core tags to drug repositioning, the inventors analyzed 3,546 drug-processing expression profile tags from the microarray chip of the CMap database for integrated analysis with the core tags. The CMap database contains microarray data of 1,309 drugs in 3 human cancer cell lines. The different cell line data for each drug were analyzed separately. Because the inventors found that, although for the same drug, only 4% had more than 100 shared differentially expressed genes in different cell lines, 37% of the drugs did not have any shared differentially expressed genes in different cell lines. This indicates that the vast majority of drugs have different expression profile signatures in different cell lines.

[0085] In order to integrate and analyze the core tags of gene mutations and drug treatment expression profile tags, the inventors evaluated the ...

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Abstract

The invention relates to a cancer genome and non-specific gene tag-based large-scale drug relocation method, and discloses a method for expression profile core labels of single human coding gene mutations without organization resource backgrounds through integrating and analyzing large-scale transcriptome data in different cancer types for the first time. On the basis of core labels, the inventionprovides a drug relocation method which aims at the in-vivo environment, is not based on model animals or cells and is capable of comprehensively covering more than 8000 human genome potential targetgenes for the first time, and designs a quantitative index for measuring interaction specificity between drugs and target genes for the first time, so that a drug relocation analysis method for comprehensively analyzing human drug target genes in a large scale is realized and a new way is provided or drug target point design and human disease treatment.

Description

technical field [0001] The invention belongs to the field of bioinformatics, and more specifically, the invention relates to a large-scale drug repositioning method based on cancer genome and non-specific gene tags. Background technique [0002] The current pharmaceutical industry faces three major challenges. First, the high cost input during drug development is out of proportion to the output of drugs that can be effectively used in clinical practice. Second, the drastic changes in the environment and the trend of population aging make the market demand for drug development is increasing day by day. Third, the current drug development is mostly based on in vitro cell screening and model animal testing, but in the end most of them are ineffective on humans or have strong side effects and cannot be used for clinical treatment. In order to speed up the drug development process and reduce risks, people are gradually turning their attention to drug repositioning research. No...

Claims

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Application Information

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IPC IPC(8): G06F19/28G06F19/24
CPCG16B40/00G16B50/00
Inventor 韩敬东徐迟
Owner SHANGHAI INST OF BIOLOGICAL SCI CHINESE ACAD OF SCI
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