TRAIL Therapy for Rhabdomyosacrcoma

横纹肌肉瘤的 TRAIL 疗法

• 批准号: 7578856
• 负责人: JANET A. HOUGHTON
• 金额: $ 23.48万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-09 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578856
• 关键词: Alveolar; Alveolar Rhabdomyosarcoma; Antibodies; Apoptosis; Binding; Caspase; Cell Death; Cell Line; Cells; Ceramides; Cessation of life; Characteristics; Childhood; Childhood Rhabdomyosarcoma; Clinical Research; Complex; Developmental Therapeutics Program; Dihydrosphingosine; Event; Genes; Goals; Human Genome; Ink; Ligands; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Mediating; Modeling; Molecular; Molecular Target; Mus; Nuclear Orphan Receptor; PAX3 gene; Patients; Phosphorylation; Proteins; Refractory; Regulation; Resistance; Rhabdomyosarcoma; Role; Science; Signal Pathway; Signal Transduction; Sphingolipids; Sphingosine; TNFRSF10B gene; TNFSF10 gene; Testing; Therapeutic; Treatment Efficacy; Xenograft procedure; base; caspase-3; caspase-8; cytotoxic; effective therapy; fusion gene; inhibitor/antagonist; kinase inhibitor; novel; novel therapeutics; outcome forecast; programs; receptor; sphingosine 1-phosphate; sphingosine kinase; t(2; 13)(q35; q14); therapeutic target; transcription factor

DESCRIPTION (provided by applicant): The prognosis for patients presenting with metastatic pediatric RMS and for those patients with ARMS harboring the PAX3/FOXO1a gene product remains poor. This renewal application explores developmental therapeutic approaches specifically for application to pediatric RMS. Five of eleven RMS cell lines are sensitive to the cytotoxic ligand TRAIL. FOXO1a, when transduced, selectively induces caspase-3 activation and apoptosis in TRAIL-resistant ARMS, and sensitizes Rh30 ARMS cells to TRAIL. The hypothesis is that these events are mediated by selective regulation via FADD, Bim or caspase-3, and may involve activation of p38 MAPK, DR5 or TRAIL. The overall goal is to elucidate downstream targets of FOXO1a that may selectively regulate apoptosis in TRAIL-resistant ARMS and may be exploitable therapeutically. SphK, which inhibits the conversion of proapoptotic Sph to SIP (involved in transformation and proliferation), is elevated in all RMS cell lines. Sph, and the SphK inhibitor, DHSph, induce apoptosis in all cell lines, independent of TRAIL, FADD, caspase-8, Bcl-2 or Bcl-xL, in contrast to Cer, which induces apoptosis in a FADD- and caspase-8-independent manner, but is inhibited by Bcl-2 or Bcl-xL. Sph and DHSph also potentiate TRAIL-induced apoptosis. The hypothesis is that Sph- or DHSph-induced apoptosis are regulated by INK activation, phosphorylation of Bcl-2, or the orphan nuclear receptor Nur77. The overall goal is to elucidate the role of SphK as a therapeutic target in both ERMS and ARMS. In addition to TRAIL, the cytolytic antibody HGS-ETR2 (Human Genome Sciences; anti-DR5) but not HGS-ETR1 (anti-DR4) is active in pediatric RMS cell lines, and DR5 is expressed at high levels. HGS-ETR2 demonstrates 1) activity superior to TRAIL, 2) formation of a large death-inducing signaling complex, 3) reduced activation of NF-KB, and 4) exquisite sensitivity in TRAIL-resistant JR1 ERMS cells. The hypothesis is that HGS-ETR2 targets a broader spectrum of RMS than TRAIL due to differences in DR5 binding or reduced influence of survival signaling pathways, and has superior activity over TRAIL either alone, in FOXO1a-transduced ARMS, or in combination with DHSph. The overall goal is to develop therapeutic approaches for both ERMS and ARMS that exploit the TRAIL signaling pathway. The long-term objectives are to develop highly effective therapy for metastatic RMS from understanding specific signaling pathways involved in the regulation of cell death, the identification of new molecular targets, and developing new therapeutic strategies based upon specific molecular characteristics.

描述（由申请人提供）：转移性儿童RMS患者和携带PAX3/FOXO1a基因产物的ARMS患者的预后仍然很差。这个更新的应用程序探索发育治疗方法，特别是应用于儿科RMS。11个RMS细胞系中有5个对细胞毒性配体TRAIL敏感。FOXO1a被转导后，在TRAIL抗性的ARMS中选择性地诱导caspase-3激活和凋亡，并使Rh30 ARMS细胞对TRAIL敏感。假设这些事件是通过FADD、Bim或caspase-3选择性调节介导的，可能涉及p38 MAPK、DR5或TRAIL的激活。总体目标是阐明FOXO1a的下游靶点，这些靶点可能选择性地调节trail耐药ARMS中的细胞凋亡，并可能用于治疗。SphK抑制促凋亡Sph向SIP（参与转化和增殖）的转化，在所有RMS细胞系中均升高。Sph和SphK抑制剂DHSph在所有细胞系中诱导细胞凋亡，不依赖TRAIL、FADD、caspase-8、Bcl-2或Bcl-xL，而Cer以FADD和caspase-8独立的方式诱导细胞凋亡，但被Bcl-2或Bcl-xL抑制。Sph和DHSph也能增强trail诱导的细胞凋亡。假设Sph-或dhsph -诱导的细胞凋亡受INK激活、Bcl-2磷酸化或孤儿核受体Nur77的调控。总体目标是阐明SphK在ERMS和ARMS中作为治疗靶点的作用。除TRAIL外，HGS-ETR2 （Human Genome Sciences; anti-DR5）而非HGS-ETR1 （anti-DR4）在儿童RMS细胞系中也有活性，DR5也有高水平表达。HGS-ETR2表现出1)活性优于TRAIL， 2)形成一个大的诱导死亡的信号复合体，3)NF-KB的激活降低，4)在TRAIL抗性的JR1 ERMS细胞中具有良好的敏感性。假设HGS-ETR2由于DR5结合的差异或生存信号通路的影响减少而比TRAIL靶向更广泛的RMS，并且在单独，foxo1a转导的ARMS或与DHSph联合中具有优于TRAIL的活性。总体目标是开发利用TRAIL信号通路的ERMS和ARMS的治疗方法。长期目标是通过了解参与细胞死亡调节的特定信号通路，识别新的分子靶点，以及基于特定分子特征开发新的治疗策略，开发出针对转移性RMS的高效治疗方法。