Optimizing Pro-Apoptotic Therapeutics With Kinase Inhibition in Neuroblastoma

通过激酶抑制优化神经母细胞瘤的促凋亡治疗

基本信息

批准号：
7624599
负责人：
Kelly C Goldsmith
金额：
$ 3.48万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2009-09-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7624599
关键词：
Affect Apoptosis Apoptotic BH3 Domain BH3 peptide Binding Biology CEP 701 Cell Line Cells Cessation of life Chemicals Chemosensitization Childhood Solid Neoplasm Clinical Co-Immunoprecipitations Data Death Domain Disabled Persons Disease Dose Drosophila pros protein EGFR inhibition Environment Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Family Family member Fostering Funding Gefitinib Goals Hydrocarbons In Vitro Knowledge Malignant Neoplasms Mediating Mentors Mitochondria Modality Modeling Modification Mus Neuroblastoma Neurotrophic Tyrosine Kinase Receptor Type 2 PI3K/AKT Pathway interactions Patients Pediatric Hospitals Pennsylvania Peptide Hydrolases Peptides Philadelphia Phosphotransferases Physicians Post-Translational Protein Processing Progressive Disease Protein Binding Protein Tyrosine Kinase Proteins Puma Reaction Relapse Relative (related person)Research Personnel Research Training Resistance Resources Scientist Serum Serum Proteins Signal Transduction Structure Therapeutic Training Programs Tyrosine Kinase Inhibitor Universities apoptosis deregulation base cancer cell career development chemotherapy conventional therapy design high risk improved in vivo inhibitor/antagonist killings kinase inhibitor member mimetics novel peptide structure prevent protein expression protein protein interaction receptor response small molecule stressor tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Neuroblastoma (NB) is a common pediatric solid tumor with high lethality. Most patients present with high-risk features and succumb to chemoresistant disease due to disabled tumor apoptosis pathways. Bcl2 homology-domain, or BH, proteins (such as Bcl2, Mcl1, Bak, and Bax) largely govern a cell's response to chemotherapy by mediating mitochondrial reaction to stressors that activate specific pro-death BH3 proteins. Many tumor types depend on altered BH protein interactions for survival. Our preliminary data shows that NB heterogeneously expresses Mcl1 and Bcl2 that may prevent apoptosis by sequestering active BH3 death signals. Further, BH3 mimetic peptides mimicking the death domain of BHS-only proteins potently induce NB apoptosis both in vitro and in vivo. Novel chemical modifications to stabilize peptide secondary structure improve serum stability and potency. We propose to exploit the knowledge of deregulated apoptotic pathways in NB to design rational pro-death therapeutic strategies with the following Aims: 1) Determine BH protein:protein interactions responsible for aberrant mitochondrial apoptosis in NB; 2) Assess the efficacy and potency of chemically modified BH3-domain peptides against NB cell lines both in vitro and in vivo; and 3) Demonstrate improved potency of BH3 peptides in these models when combined with tyrosine kinase inhibitors targeting receptors that mediate survival, proliferation and chemoresponse in neuroblastoma. This proposal lays out a 5-year research and training program that will help the principle investigator transition to become an independent researcher with the ultimate goal of becoming an R01-funded physician-scientist. Her mentors and advisors are leaders in the field of apoptosis, neuroblastoma, and experimental therapeutics. She will take advantage of the ample resources offered through the environments of both the Children's Hospital of Philadelphia and the University of Pennsylvania to foster her career development. Relevance. Neuroblastoma is a highly lethal tumor with no curative therapy following relapse. Current treatments are ineffective and new treatment depends on the identification of therapies that target tumor-specific biology. BH3 peptides that potently kill NB and other cancer cells prove promising as translational pro-death therapeutics given recent novel chemical modifications to improve peptide structure. Combining BH3 peptides with clinically available kinase inhibitors demonstrates that targeting both survival signaling and apoptosis using rationally chosen agents will provide a novel and effective approach to treating cancers resistant to current conventional treatment modalities.

描述（由申请人提供）：神经母细胞瘤（NB）是一种常见的儿科实体瘤，具有高致死性。大多数患者具有高风险特征，并且由于肿瘤凋亡途径而屈服于化学抗性疾病。 Bcl2同源性域或BH，蛋白（例如Bcl2，MCL1，BAK和BAX）在很大程度上主要控制了细胞对化学疗法的反应，通过介导线粒体对激活特定pro Death BH3蛋白的压力因子的反应。许多肿瘤类型取决于BH蛋白相互作用的改变以生存。我们的初步数据表明，NB异质表达MCL1和BCL2，这些MCL1和BCL2可能通过隔离活性BH3死亡信号来阻止凋亡。此外，BH3模拟肽模仿仅BHS蛋白质的死亡结构域，在体外和体内都有效诱导NB凋亡。稳定肽二级结构的新型化学修饰可提高血清稳定性和效力。我们建议利用NB中放松管制的凋亡途径的知识来设计有理死亡的治疗策略，其目的是：1）确定BH蛋白质：蛋白质相互作用：蛋白质相互作用，导致NB中的线粒体异常凋亡。 2）评估化学改性的BH3核肽对NB细胞系的疗效和效力，无论是体外和体内的； 3）当这些模型与酪氨酸激酶抑制剂靶向介导神经母细胞瘤中介导存活，增殖和化学响应的受体时，证明了BH3肽的效力提高。该提案制定了一项为期5年的研究和培训计划，该计划将有助于主要研究者过渡成为独立研究人员，其最终目标是成为R01资助的医师 - 科学家。她的导师和顾问是细胞凋亡，神经母细胞瘤和实验疗法领域的领导者。她将利用费城儿童医院和宾夕法尼亚大学的环境中提供的充足资源，以促进她的职业发展。关联。神经母细胞瘤是一种高度致命的肿瘤，复发后没有治疗疗法。当前的治疗方法无效，新疗法取决于鉴定靶向肿瘤特异性生物学的疗法。有效杀死NB和其他癌细胞的BH3肽被证明是转化促疾病疗法，鉴于最近的新型化学修饰以改善肽结构。将BH3肽与临床上可用的激酶抑制剂组合在一起表明，使用合理选择的药物靶向生存信号传导和凋亡将提供一种新颖有效的方法，可治疗对当前常规治疗方式的耐药性。