Abstract ▼

Purpose
- Identification of gene and protein expression markers along major cancer genotype
- Understanding statistical correlation between genotype and drug sensitivity using diverse cancer types and drugs
- Suggestion of genotype applicable to novel target therapy and drug repositioning t

Purpose
- Identification of gene and protein expression markers along major cancer genotype
- Understanding statistical correlation between genotype and drug sensitivity using diverse cancer types and drugs
- Suggestion of genotype applicable to novel target therapy and drug repositioning through combination screening of previous and new compound
- Confirmation of for drug sensitivity affected by TP53 mutation in different cancer types and genotype
Contents
Analysis of genotype-dependent drug sensitivity and DB construction using CLEA
- Securing DNA microarray, RPPA (Reverse Phase Protein Array), drug response data on hundreds of cancer cell lines form MD Anderson, NCI, GSK. Construction of regular annotation for Lineage, Mutation, Gene amplification based on Sanger COSMIC DB and genotyping by MD Anderson
- Applying CLEA (Cell Line Enrichment Analysis) analysis, genotype-based classification of cancer cell lines and identification of genotype-dependent drug sensitivity and differentiated pattern of omics data
- Analysis of drug sensitivity and resistance along major 17 genotype for >40,000 compounds of NCI60 and 34 drugs of GSK dataset.
- From analysis of GSK dataset, confirmation of significant correlation between IGF1R, MEK, and PI3K target drugs and related genotype.
- In addition, identification of novel relationship between drug and genotype. IGF1R inhibitor represented high sensitivity to MYC-amplification and NRAS mutation and PI3K target drug showed ERBB2-Amp and PIK3CA mutation-sensitive response.
- Confirmation of clustered pattern for major 10 genotype along TP53 wild and mutant type from analysis of combined mutation pairs centered on TP53.
- Through this analysis, suggestion of important role of TP53 in evaluation of drug.
- Construction of web DB using chemical information for >40,000 compounds and data value of its GI50 and drug sensitivity in NCI60 dataset(http://lage.sookmyung.ac.kr/~MSEA).
Integration of cell line-based transcriptome and proteome with CLEA analysis
- Genotype-dependent correlation analysis of cell line-based transcriptome and proteome applying CLEA
- Analysis of genotype-specific gene expression, protein expression and phosphorylation patterns and integration with genotype-dependent drug sensitivity
- The network analysis of transcriptome and proteome along drug sensitivity and systematic understanding of genotype-dependent drug sensitivity in the level of gene and protein expression
Identification of cancer characteristic (genotype)-related gene markers
－ Correlation analysis of cancer genotype and gene expressional change through transcriptome analysis obtained from GSK(GlaxoSmithKline)
－ Identification of 5 gene markers with STK11 mutation-sensitive expression in lung cancer and validation using siRNA and cell viability assay
－ Adapting whole genome siRNA library screening, comprehension of gene expression pattern along genotype and drug sensitivity
－ Suggestion of analytical system based on diverse cancer genotype over previous cancer type-dependent analysis
Expected Contribution
－ Securing systematic information for drug sensitivity based on cancer types and genotype
－ Understanding of predictable markers of drug sensitivity in the level fo gene and protein expression and phosphorylation
－ Probability of novel drug repositioning for new genotype through drug combination

목차 Contents

• 표지 ... 1
• 제출문 ... 2
• 목차 ... 3
• 연구개발사업 최종연구개발결과보고서 요약문 ... 4
• Project Summery ... 6
• 1. 연구과제의 최종 연구개발 목표 ... 8
• 연구 배경 및 필요성 ... 8
• 연차별 연구 목표 및 범위 ... 9
• 2. 연구과제의 연구대상 및 방법 ... 10
• 암 세포주에 대한 유전형 분류 ... 10
• 약물 반응 및 전사체, 단백질체 데이터 확보 ... 11
• CLEA를 이용한 시스템 수준의 유전형과 약물민감도 상관관계 분석 ... 12
• 3. 연구과제의 연구개발결과 ... 14
• 단일 유전형에 따른 약물 반응 분석 ... 14
• TP53 co-mutation에 따른 약물 반응 분석 ... 16
• CLEA DB 구축 ... 17
• CLEA 약물 민감도 결과와 전사체, 단백질체 데이터의 통합 분석 ... 18
• 유전형 기반 시스템 수준에서의 약물 민감도 이해 ... 19
• 전사체 데이터를 활용한 유전형 특이적 유전자 지표 발굴 ... 20
• Human siRNA library 스크리닝 ... 23
• NCI60 데이터를 활용한 화합물 구조와 돌연변이 특이적 암 세포 민감도 분석 ... 24
• 4. 연구과제의 연구결과 고찰 및 결론 ... 27
• 5. 연구과제의 연구성과 및 목표달성도 ... 28
• (1) 연구성과 총괄 ... 28
• (2) 연구성과 상세내역 ... 29
• (3) 연구개발과제의 목표달성도 ... 34
• 6. 연구과제의 활용계획 ... 35
• (1) 연구종료 3년까지 예상 연구성과 ... 35
• (2) 연구성과의 활용계획 ... 35
• 7. 참고문헌 ... 36
• 8. 첨부서류 ... 37
• 끝페이지 ... 39