Hsp90 as a Target for the Treatment of Childhood Cancer

申请人简介(申请人提供)：申请人Rochelle Bagatell博士是一名儿科肿瘤学家，致力于以患者为中心的研究事业，专注于儿童癌症的分子靶向治疗研究。几种靶向肿瘤细胞信号转导通路的药物已被发现对成人癌症的治疗有效，但这些药物尚未在儿童中广泛研究。考虑到在强化治疗后恶性肿瘤复发的儿童预后不佳，需要更新、毒性更低的药物。改变热休克蛋白90(Hsp90)功能的药物可以提供一种有效的方法来抑制促进癌细胞存活的信号通路。HSP90在应激耐受、蛋白质折叠和翻译后控制细胞生长、分化和凋亡的许多关键调节因子的稳定性和功能方面发挥着重要作用。Hsp90抑制剂的原型格尔达那霉素与Hsp90结合，这样做会导致受Hsp90调控的关键癌症相关蛋白水平发生变化。肝脏毒性禁止在体内使用这种药物，但临床上相关的格尔达霉素衍生物目前正在进行临床试验。17-dimethylaminoethylamino-17-demethoxygeldanamycin(17-DMAG；NSC 707545)是一种具有良好药理性质的格尔达霉素衍生物。这类药物在儿童恶性肿瘤的治疗中特别令人感兴趣，因为它们导致儿童肿瘤中重要的信号分子水平显著下降，然而17-DMAG以前从未被用于儿童。为了实现为癌症儿童确定有效的分子靶向制剂这一长期目标，并实现申请者的职业发展目标，设计了这一研究项目。1)评价17-DMAG在体内外对儿童实体瘤细胞的抗癌活性，以及DMAG治疗后HspQO相关关键蛋白水平的变化。2)对复发或难治性恶性肿瘤患者进行作为单一药物的17-DMAG的I期试验，并测量17-DMAG目标蛋白水平的变化。试验的主要目标将是确定17-DMAG在这些患者中的剂量限制毒性(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、IGF1R和HSP72水平的程度。3)评价Hsp90抑制剂与其他抗癌药物在儿童实体瘤临床前模型中的联合应用，并探讨其增强抗癌作用的机制。拟议的研究项目是精心构建和多方面的职业发展计划的一部分，该计划的重点是评估用于治疗儿童癌症的分子靶向药物。申请者将通过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。她还将在进行翻译研究和临床试验方面获得实践经验，并将开展临床前工作，为未来具有强大翻译成分的临床试验奠定基础。在获奖期结束后，巴格特尔博士将做好充分准备，成为一名独立的调查员。

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.