초록 ▼

종양 발생에 중요한 역할을 하는 수용체 티로신 카이네이즈를 타겟팅하는 다양한 항암제가 개발되어 임상에서 사용되고 있지만, 다수의 환자들에서 수용체 티로신 카이네이즈 내성이 나타나 치료에 어려움을 겪고 있음 뇌종양 발생 및 재발 원인으로 이해되는 뇌종양줄기세포에서 ID4에 의한 다중 수용체 티로신 카이네이즈[multiple receptor tyrosine kinases (multiple-RTKs)]의 활성기전을 규명함으로써 현재 임상에서 제시되고 있는 RTK inhibitors들의 복합 치료를 대체할 수 있는 통합조절인자 (One-f

종양 발생에 중요한 역할을 하는 수용체 티로신 카이네이즈를 타겟팅하는 다양한 항암제가 개발되어 임상에서 사용되고 있지만, 다수의 환자들에서 수용체 티로신 카이네이즈 내성이 나타나 치료에 어려움을 겪고 있음 뇌종양 발생 및 재발 원인으로 이해되는 뇌종양줄기세포에서 ID4에 의한 다중 수용체 티로신 카이네이즈[multiple receptor tyrosine kinases (multiple-RTKs)]의 활성기전을 규명함으로써 현재 임상에서 제시되고 있는 RTK inhibitors들의 복합 치료를 대체할 수 있는 통합조절인자 (One-for-All inhibitor)를 발굴하여 multiple-RTK 표적지향성 치료의 효율을 높일 수 있는 방안을 제시함 추가적으로 ID4-OCT4 신호 기전을 통해 최근 대두되고 있는 암줄기세포와 혈관 미세 환경과의 상호작용을 밝혔고, E3 ubiqutin ligase인 Cullin3 신호 조절을 통해 암줄기세포를 표적화 하는 치료 방안을 제시함

Abstract ▼

Ⅰ. Purpose and contents
The purpose of this study is to suggest a means by which the efficacy of multiple-RTKs targeted therapy can be incremented. This is to be preceded by validating the activation mechanisms of multuple-RTKs in glioma stem cells which are understood as one of the primary cause

Ⅰ. Purpose and contents
The purpose of this study is to suggest a means by which the efficacy of multiple-RTKs targeted therapy can be incremented. This is to be preceded by validating the activation mechanisms of multuple-RTKs in glioma stem cells which are understood as one of the primary causes of tumor progression and recurrence, and excavating One-for-all inhibitor that can replace the currently used combination therapy of multiple-RTK inhibitors.

Ⅱ. Results
1. Analysis of mechanism with the regulation of multiple RTKs (PDGFR, EGFR, MET, AXL, ErbB2) in ID4 overexpressing or ID4 knockdown cancer cells
2. Analysis of mechanism with mutual regulation of ID4 and PDGFR, and validation the mechanism by which multiple RTKs (PDGFR, EGFR, MET, AXL, ErbB2) are activated by PDGFR
3. Analysis of mechanism with the upregulation of multiple RTKs (PDGFR, EGFR, MET, AXL, ErbB2) in protein levels by ID4
4. Characterization of biological roles of multiple RTKs (PDGFR, EGFR, MET, AXL, ErbB2) in the regulation of cell growth, drug resistance and tumorshpre formation in cancer stem cells
5. Establishment therapeutic targets against ID4 and multiple RTKs signals for development of cancer stem cell-specific therapy
6. Analysis the clinical correlation between the expression patterns of candidate signal molecules and survival from the TCGA database and human GBM patient samples
7. Analysis of mechanism with ID4-OCT4 in cancer stem cell perivascular niche
8. Analysis efficacy of cullin3 that suppress cancer stem cell initiation, GBM development in vivo and in vitro GBM models

Ⅲ. Expected Contribution
1. This study could render great contributions to our understanding for mechanism underlying all of current challege and controversy, such as the cancer stem cell inducing factors, cancer stem cell niche and drug resistance.
2. In contrast to classical paradigm for development of anticancer therapeutics against cancer cells, this study as an excellent model system could broadly stimulate identification of new molecular targets, anticancer drug design, and screening against cancer stem cells, ultimately leading to minimize losses of economical, social, and industrial losses.