Hsp90 as a Target for the Treatment of Childhood Cancer

Hsp90 作为儿童癌症治疗的靶点

• 批准号: 7678489
• 负责人: ROCHELLE BAGATELL
• 金额: $ 11.94万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678489
• 关键词: Adolescent; Adult; Animals; Antineoplastic Agents; Apoptosis; Arizona; Award; Binding; Blood specimen; Cancer Biology; Cause of Death; Cell Line; Cell Survival; Cells; Characteristics; Chemotherapy-Oncologic Procedure; Child; Childhood; Childhood Solid Neoplasm; Clinical; Clinical Research; Clinical Trials; Commit; Data; Detection; Development; Development Plans; Disease; Dose; Dose-Limiting; Doxorubicin; Drug Combinations; Ensure; Evaluation; Ewings sarcoma; Foundations; Future; Geldanamycin; Goals; Growth; Heat-Shock Proteins 90; Hepatotoxicity; IGF1R gene; In Vitro; Insulin-Like-Growth Factor I Receptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Molecular Target; Mus; Neuroblastoma; Non-accidental; Patients; Pattern; Pediatric Neoplasm; Pediatric Oncologist; Pediatric Oncology; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Platinum; Play; Pre-Clinical Model; Property; Proteins; Publishing; Recurrence; Refractory; Relapse; Research; Research Personnel; Research Project Grants; Research Training; Resources; Role; School-Age Population; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Solid; Solid Neoplasm; Staging; Structure; Testing; Toxic effect; Training; Training Programs; Translational Research; Treatment Protocols; Tumor Cell Line; Universities; Work; anticancer activity; cancer cell; cancer therapy; career; career development; cell growth; clinically relevant; design; experience; in vivo; inhibitor/antagonist; insight; interest; neoplastic cell; osteosarcoma; outcome forecast; oxaliplatin; patient oriented research; pre-clinical; programs; protein folding; prototype; research study; skills; stress tolerance; tumor; tumor growth; tumor xenograft

DESCRIPTION (provided by applicant): The applicant, Dr. Rochelle Bagatell, is a pediatric oncologist who is committed to pursuing a career in patient oriented research, with a focus on the study of molecularly targeted therapies for pediatric cancer. Several agents that target signal transduction pathways in tumor cells have been found to be effective in the treatment of cancers in adults, but these agents have not been widely studied in children. Given the dismal prognosis for children whose malignancies recur following intensive therapy, newer and less toxic drugs are needed. One effective approach to inhibiting signaling pathways that promote cancer cell survival could be provided by drugs that alter the function of heat shock protein 90 (Hsp90). Hsp90 plays an essential role in stress tolerance, protein folding and post-translational control of the stability and function of many key regulators of cell growth, differentiation and apoptosis. Geldanamycin, the prototype Hsp90 inhibitor, binds to Hsp90 and in so doing causes alterations in levels of key cancer-associated proteins that are regulated by Hsp90. Hepatotoxicity prohibits the use of this agent in vivo, however clinically relevant geldanamycin derivatives are currently in clinical trials. 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17- DMAG; NSC 707545) is a geldanamycin derivative with favorable pharmaceutical properties. Agents of this class are of particular interest in the treatment of pediatric malignancies because they cause a marked decrease in levels of signaling molecules that are important in childhood tumors, however 17-DMAG has never previously been administered to children. As part of an effort to achieve the long-term goal of identifying effective molecularly targeted agents for children with cancer, and to achieve the career development goals of the applicant, this research project has been designed. The specific aims proposed are: 1) To evaluate the anticancer activity of 17-DMAG against pediatric solid tumor cells in vitro and in vivo, and to evaluate changes in levels of key HspQO-related proteins following DMAG treatment. 2) To conduct a Phase I trial of 17-DMAG as a single agent in patients with recurrent or refractory malignancies and to measure changes in levels of 17-DMAG target proteins. Primary objectives of the trial will be to establish the Dose Limiting Toxicity (DLT) and the Maximum Tolerated Dose (MTD) of 17-DMAG in these patients and to assess the extent to which the MTD of this drug alters the levels of Akt, IGF1R, and Hsp72 in blood samples. 3) To evaluate combinations of Hsp90 inhibitors and other anticancer agents in pre-clinical models of pediatric solid tumors, and to investigate the mechanisms underlying augmented anti-cancer effects. The proposed research project is part of a carefully structured and multi-faceted career development plan that focuses on the evaluation of molecularly targeted agents for the treatment of childhood cancers. The applicant will receive didactic training through the K30-supported Arizona Clinical Research Training Program and through courses in Pharmacology and Cancer Biology. She will also gain practical experience in the conduct of translational research and clinical trials, and will perform pre-clinical work that will lay the foundation for future clinical trials with strong translational components. Upon completion of the award period, Dr. Bagatell will be well prepared to move forward as an independent investigator.

描述（由申请人提供）：申请人罗谢尔·巴加特尔博士是一名儿科肿瘤学家，致力于从事以患者为导向的研究，重点研究儿科癌症的分子靶向治疗。已经发现靶向肿瘤细胞中的信号转导通路的几种药物在成人癌症的治疗中是有效的，但这些药物尚未在儿童中进行广泛的研究。由于恶性肿瘤在强化治疗后复发的儿童预后不良，需要更新和毒性较小的药物。抑制促进癌细胞存活的信号通路的一种有效方法可以通过改变热休克蛋白90（Hsp 90）功能的药物来提供。热休克蛋白90在细胞生长、分化和凋亡的许多关键调节因子的稳定性和功能的应激耐受、蛋白质折叠和翻译后控制中起重要作用。Geldanamycin是Hsp 90抑制剂的原型，它与Hsp 90结合，从而导致受Hsp 90调节的关键癌症相关蛋白水平的改变。肝毒性禁止在体内使用该药物，但临床相关的格尔德霉素衍生物目前正在临床试验中。17-二甲氨基乙氨基-17-去甲氧基格尔德霉素（17- DMAG; NSC 707545）是一种具有良好药物性质的格尔德霉素衍生物。这类药物在儿科恶性肿瘤的治疗中特别令人感兴趣，因为它们引起在儿童肿瘤中重要的信号分子水平的显著降低，然而17-DMAG以前从未被施用于儿童。为了实现为癌症儿童确定有效的分子靶向药物的长期目标，并实现申请人的职业发展目标，设计了本研究项目。提出的具体目的是：1）评估17-DMAG对儿科实体瘤细胞的体外和体内抗癌活性，并评估DMAG治疗后关键HspQO相关蛋白水平的变化。2)在复发性或难治性恶性肿瘤患者中进行17-DMAG单药治疗的I期试验，并测量17-DMAG靶蛋白水平的变化。试验的主要目的是确定17-DMAG在这些患者中的剂量限制性毒性（DLT）和最大耐受剂量（MTD），并评估该药物的MTD改变血液样本中Akt、IGF 1 R和Hsp 72水平的程度。3)评价Hsp 90抑制剂和其他抗癌药物在儿科实体瘤临床前模型中的组合，并研究增强抗癌作用的机制。拟议的研究项目是一个精心设计和多方面的职业发展计划的一部分，重点是评估用于治疗儿童癌症的分子靶向药物。申请人将通过K30支持的亚利桑那州临床研究培训计划以及药理学和癌症生物学课程接受教学培训。她还将获得转化研究和临床试验方面的实践经验，并将开展临床前工作，为未来具有强大转化成分的临床试验奠定基础。在奖励期结束后，Bagatell博士将做好充分准备，作为一名独立的研究人员向前迈进。