Novel Therapeutic Strategy for Refractory and Relapse Childhood Acute Leukemia

难治性和复发性儿童急性白血病的新治疗策略

基本信息

批准号：
8523613
负责人：
Martin F Haslanger
金额：
$ 24.03万
依托单位：
APEX THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523613
关键词：
Acute Lymphocytic Leukemia Acute T Cell Leukemia Acute leukemia Address Adult Acute Lymphocytic Leukemia Animal Model Animals Apoptosis Biochemical Biological Availability Cause of Death Cell Survival Cells Cellular biology Cessation of life Chemistry Child Childhood Childhood Acute Lymphocytic Leukemia Childhood Leukemia Coupled DNA Repair Data Development Dexamethasone Disease Disease remission Dose Down-Regulation Drug Kinetics Drug resistance Generations Genes Genetic Transcription Glioblastoma Glucocorticoids Goals Grant Growth In Vitro Infant Injectable Intervention Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of pancreas Manuscripts Mediating Medical Medicine Metabolism Modeling Molecular Molecular Biology Mus Nuclear Oncogenic Oral Oxidation-Reduction Pathway interactions Patients Pharmaceutical Preparations Play Preparation Primary Neoplasm Proteins Recurrence Recurrent disease Refractory Refractory Disease Relapse Resistance Role STAT3 gene Signal Pathway Signal Transduction Solid Neoplasm T-Cell Leukemia Testing Therapeutic Therapeutic Agents Transcription Factor AP-1 Treatment Efficacy Xenograft procedure anti-cancer therapeutic conventional therapy drug development effective therapy in vivo in vivo Model inhibitor/antagonist interest leukemia meetings neoplastic cell notch protein novel novel therapeutics outcome forecast programs public health relevance response transcription factor tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to develop a novel therapeutic strategy for childhood acute lymphoblastic leukemia (ALL), with focus on relapsed T-cell leukemia. We intend to accomplish this by targeting a unique molecular master regulator using a new generation of compounds. ALL is the most frequent cancer of the childhood. Although significant progress has been achieved with conventional therapies, major therapeutic challenges remain, including infant ALL, leukemia relapse and refractory disease. Overall, relapsed ALL is associated with poor prognosis, is per se the fourth most frequent childhood cancer and remains the second leading cause of childhood death; therefore, more effective therapies are much needed. As for other cancers, increasing evidence indicates that effective therapies for relapsed ALL will require the targeting of distinct molecular pathways. The central hypotheses of this grant is that the redox factor Ref-1 regulates critical transcription programs mediating the survival of relapsed leukemia cells, and that the selective blockade of Ref-1 redox function effectively inhibits leukemia recurrence and progression in animal models of relapse childhood ALL. This is supported by multiple evidence on the regulatory role of Ref-1 on important downstream targets involved in cancer growth, metabolism and drug resistance (NF-?B, AP-1, HIF-1¿, STAT3), coupled with our previous studies with E3330 as a specific Ref-1 redox inhibitor and our preliminary data on T-cell ALL and leukemia relapse. To attain our goals we propose the following specific aim: Specific Aim 1. To determine the therapeutic efficacy of Ref-1 redox blockade in animal models of relapsed childhood ALL using novel Ref-1 inhibitors. We will perform studies to investigate the anti-leukemia efficacy of our novel Ref-1 redox inhibitors in two distinct models of childhood relapsed ALL: a) xenografts with T-ALL cells from relapsed patients and, b) model of Notch-induced T-cell leukemia with disease recurrence after Dexamethasone treatment. We anticipate that our newly identified Ref-1 selective redox inhibitors will show significant anti-leukemia efficacy in the in vivo models of relapsed T-cell leukemia, with increased animal survival. While our model and the focus in this application is relapsed childhood ALL, we anticipate that these inhibitors will have additional indications in other cancers where Ref-1 has been implicated, e.g. pancreatic cancer, glioblastoma, as well as in other relapsed childhood leukemia and in adult ALL.

描述（由申请人提供）：我们的长期目标是开发一种针对儿童急性淋巴细胞白血病（ALL）的新型治疗策略，重点关注复发性 T 细胞白血病。我们打算通过使用独特的分子主调节因子来实现这一目标。 ALL 是最常见的儿童癌症，尽管传统疗法已取得重大进展，但仍存在重大治疗挑战，包括婴儿 ALL、白血病复发和难治性疾病。与不良预后相关，本身是第四大最常见的儿童癌症，并且仍然是儿童死亡的第二大原因；因此，对于其他癌症，越来越多的证据表明需要有效的治疗复发性 ALL。该资助的中心假设是氧化还原因子 Ref-1 调节介导复发性白血病细胞存活的关键转录程序，并且选择性阻断 Ref-1 氧化还原功能可有效抑制白血病的复发和进展。动物Ref-1 对涉及癌症生长、代谢和耐药性的重要下游靶点（NF-?B、AP-1、HIF-1¿）的调节作用的多项证据支持了这一点。，STAT3），结合我们之前使用 E3330 作为特定 Ref-1 氧化还原抑制剂的研究以及我们关于 T 细胞 ALL 和白血病复发的初步数据，为了实现我们的目标，我们提出以下具体目标：具体目标 1. 确定。使用新型 Ref-1 抑制剂在复发性儿童 ALL 动物模型中进行 Ref-1 氧化还原阻断的治疗效果我们将开展研究，以研究我们的新型 Ref-1 氧化还原抑制剂在两种不同模型中的抗白血病功效。儿童复发性 ALL 的模型：a) 来自复发患者的 T-ALL 细胞异种移植物，b) Notch 诱导的 T 细胞白血病模型，在地塞米松治疗后疾病复发。我们预计我们新鉴定的 Ref-1 选择性氧化还原抑制剂将显示出效果。在复发性 T 细胞白血病体内模型中具有显着的抗白血病功效，并增加了动物存活率。虽然我们的模型和本应用的重点是复发性儿童 ALL，但我们预计这些抑制剂将能够发挥作用。在涉及 Ref-1 的其他癌症中还有其他适应症，例如胰腺癌、胶质母细胞瘤以及其他复发性儿童白血病和成人 ALL。