Tumor Selective Apoptosis by TRAIL

TRAIL 肿瘤选择性凋亡

• 批准号: 7743314
• 负责人: ROYA KHOSRAVI-FAR
• 金额: $ 64.7万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7743314
• 关键词: Affinity; Amino Acids; Apoptosis; Apoptotic; Biological Availability; Biological Process; CASP8 and FADD-like apoptosis regulating protein; Cell Culture Techniques; Cells; Cessation of life; Chemicals; Classification; Clinical; Complex; Cyclic Peptides; Development; Effectiveness; Epitopes; Failure; Funding; Goals; Hematologic Neoplasms; Hydrogen Bonding; Lead; Ligands; Malignant Neoplasms; Mediating; Modeling; Molecular; Peptides; Pharmaceutical Preparations; Play; Property; Resistance; Role; Scanning; Screening procedure; Series; Side; Signal Transduction; Specificity; Structure-Activity Relationship; TNFRSF10B gene; TNFSF10 gene; Therapeutic; Variant; Vertebral column; cancer cell; cancer type; caspase-8; chemotherapeutic agent; design; drug synthesis; effective therapy; improved; in vivo; innovation; knock-down; mouse model; neoplastic cell; novel; overexpression; peptidomimetics; pharmacophore; pre-clinical; receptor; scaffold; tumor

c-FLIP is a key anti-apoptotic factor that is over-expressed in many tumors and blocks the apoptotic machinery by interfering with FADD, caspase-8 and DR5. Significant evidence demonstrates that c-FLIP over-expression in tumors is a major cause of resistance to TRAIL-induced apoptosis. Therefore, strategies to inhibit c-FLIP action and to overcome c-FLIP-induced resistance in tumor cells may lead to novel and more effective therapies. We have discovered a bioactive peptide, ApoFLIP that antagonizes with c-FLIP and reinstates the apoptotic machinery in c-FLIP expressing cells. The major goal of this proposal is to develop and characterize drug-like variants of this peptide. These agents could provide significant enhancements in the current therapeutic strategies in hematological malignancies and other tumors that show resistance to apoptosis-inducing therapeutics.

c-FLIP是一种关键的抗凋亡因子，在许多肿瘤中过表达，并通过干扰FADD、caspase-8和DR 5来阻断凋亡机制。大量证据表明，c-FLIP在肿瘤中的过表达是对TRAIL诱导的细胞凋亡产生抗性的主要原因。因此，抑制c-FLIP作用和克服c-FLIP诱导的肿瘤细胞耐药性的策略可能会导致新的和更有效的治疗。我们已经发现了一种生物活性肽ApoFLIP，其拮抗c-FLIP并恢复表达c-FLIP的细胞中的凋亡机制。该提案的主要目标是开发和表征这种肽的药物样变体。这些药物可以显著增强血液恶性肿瘤和其他对诱导凋亡的治疗药物具有耐药性的肿瘤的当前治疗策略。