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Tumor Selective Apoptosis by TRAIL

TRAIL 肿瘤选择性凋亡

基本信息

批准号：
7930578
负责人：
ROYA KHOSRAVI-FAR
金额：
$ 63.2万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7930578
关键词：
Agonist Amino Acids Antibodies Apoptosis Apoptosis Inhibitor Apoptotic CASP8 and FADD-like apoptosis regulating protein Cancer Model Cell Culture Techniques Cell membrane Cells Cessation of life Chemicals Clinical Colon Carcinoma Complex Cyclic Peptides Development Effectiveness Failure Funding Goals Hematologic Neoplasms Hydrogen Bonding Intervention Lead Ligands Malignant Neoplasms Mediating Modeling Molecular Pathway interactions Peptides Pharmaceutical Preparations Play Pre-Clinical Model Research Resistance Role Scanning Screening procedure Series Side Signal Transduction Sum TNFRSF10B gene TNFSF10 gene Therapeutic Toxic effect Treatment Protocols Variant Vertebral column Xenograft procedure cancer cell cancer type caspase-8 chemotherapeutic agent design drug synthesis effective therapy improved in vivo innovation knock-down mouse model neoplastic cell novel oncology overexpression peptidomimetics pharmacophore pre-clinical prevent receptor scaffold tumor

项目摘要

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DR5来阻断凋亡机制。大量证据表明，c-flip在肿瘤中的过度表达是抵抗TRAIL诱导的细胞凋亡的主要原因。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带来新的和更有效的治疗方法。我们已经发现了一种生物活性多肽ApoFLIP，它可以与c-Flip拮抗，并恢复c-Flip表达细胞的凋亡机制。这项提案的主要目标是开发和鉴定这种多肽的药物样变异体。这些药物可以为血液系统恶性肿瘤和其他对凋亡诱导疗法表现出抵抗力的肿瘤的当前治疗策略提供显著的增强。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Combination of bortezomib and mitotic inhibitors down-modulate Bcr-Abl and efficiently eliminates tyrosine-kinase inhibitor sensitive and resistant Bcr-Abl-positive leukemic cells.

DOI：
10.1371/journal.pone.0077390
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Bucur O;Stancu AL;Goganau I;Petrescu SM;Pennarun B;Bertomeu T;Dewar R;Khosravi-Far R
通讯作者：
Khosravi-Far R

Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities.