Targeting non-classical oncogenes as therapy for T-ALL

针对非经典癌基因治疗 T-ALL

基本信息

批准号：
8680039
负责人：
Thomas G Diacovo
金额：
$ 32.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680039
关键词：
1-Phosphatidylinositol 4-Kinase Acute Acute Lymphocytic Leukemia Acute T Cell Leukemia Address Adolescent Adult Animal Model Animals Binding Biochemical Genetics Biological Process Blood CD34 gene Catalytic Domain Cell Cycle Progression Cell Line Cell Proliferation Cell Survival Cells Chemicals Child Chromosome abnormality Clinic Clinical Treatment Clinical Trials Combination Drug Therapy Computer Simulation Development Disease Disease Resistance Docking Drug Combinations Drug resistance Functional disorder Gatekeeping Gene Chips Genetic Models Gleevec Goals Growth Hematologic Neoplasms Hormonal Human IL7R gene Imatinib Immune response Immunocompetence Knowledge Laboratories Late Effects Lead Lymphoblastic Leukemia Lymphocyte Subset Malignant - descriptor Modeling Mutagenesis Mutation Nature Oncogenes Organ PTEN gene Pathogenesis Pathway interactions Patients Peripheral Pharmaceutical Preparations Phosphatidylinositols Phosphotransferases Play Point Mutation Process Protein Biosynthesis Protein Isoforms Refractory Relapse Reporting Research Methodology Resistance Role Sampling Second Primary Cancers Seminal Signal Pathway Stem cells Structure T cell therapy T-Cell Development T-Cell Transformation T-Lymphocyte Testing Thymus Gland Time Translating Vulnerable Populations Work Xenograft Model addiction base cancer therapy chemical binding chemotherapy comparative genomic hybridization drug sensitivity genetic analysis improved inhibitor/antagonist kinase inhibitor neoplastic cell novel novel therapeutics progenitor reproductive response small molecule treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer that occurs in children as well as adults. Despite intensive therapies, 25% of children and adolescents and 50% of adults with T-ALL will ultimately succumb to the disease. Moreover, the late effects of cancer treatment, including permanent organ damage, hormonal and reproductive dysfunction, and second cancers are a special concern in children as current therapies indiscriminately target all dividing cells. The goal of this proposal is to identify and therapeutically target a pathway that is essential for the growth and survival of T-ALL, the inhibition of which will be considerably less toxic than standard chemotherapy. Class I phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been reported to be activated in over 40% of cases of T-ALL. Although four distinct class I PI3K isoforms could participate in T-ALL pathogenesis, none have been implicated in this process. Using genetically altered animals and novel small molecule inhibitors, we have identified specific isoforms that appear to be essential for the development and survival of T- ALL. Based on these observations, we propose that it is possible to exploit the "addiction" of this hematological malignancy to these particular PI3K isoforms as a new therapeutic avenue for T-ALL. To achieve these objectives, we propose the following specific aims: Aim 1. To determine the efficacy and to define the mechanism(s) of action by which 2 novel isoform specific PI3K inhibitors may impact on T-ALL pathogenesis. This will be accomplished by evaluating the effects of these inhibitors in an animal model of PTEN null T-ALL, on human T-ALL cell lines, and on primary patient samples. Emphasis will be placed on interrogating downstream pathways that regulate cell cycle progression, protein synthesis, and cell survival using a combination of biochemical and genetic approaches. Aim 2. To uncover potential PI3K-dependent and independent mechanisms that may result in secondary resistance. This includes identifying resistance-conferring point mutations and alternative signaling pathways using in silico models of drug binding, chemical-induced mutagenesis, and drug-induced resistant disease in animals. Biochemical and genetic analyses will be performed, the latter including gene expression microarrays and array-based comparative genomic hybridization. Aim 3. To determine the effects of isoform specific PI3K inhibitors on the development, peripheral expansion, survival and function of human T cells. This will be accomplished by evaluating drug effects in a unique human thymus/CD34+ stem cell xenograft model.

描述（由申请人提供）： T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性的血液学癌症，发生在儿童和成人中。尽管进行了密集的疗法，但有25％的儿童和青少年和50％的T-All成年人最终会屈服于该疾病。此外，癌症治疗的后期作用，包括永久器官损伤，荷尔蒙和生殖功能障碍以及第二癌的癌症治疗，因为当前疗法不加选择地针对所有分裂细胞，儿童是儿童的特别关注点。该提案的目的是识别和治疗目标，该途径对于T-ALL的生长和存活至关重要，其抑制作用将比标准化疗的毒性要小得多。 I类磷酸肌醇3-激酶（PI3K）/AKT信号传导途径已在40％的T-ALL病例中被激活。尽管四个不同的I类PI3K同工型可以参与T-ALL发病机理，但在此过程中却没有任何涉及。使用遗传改变的动物和新型的小分子抑制剂，我们已经确定了似乎对于T-全部的发展和存活至关重要的特定同工型。基于这些观察结果，我们建议可以利用这种血液性恶性肿瘤的“成瘾”对这些特定的PI3K同工型作为T-ALL的新治疗途径。为了实现这些目标，我们提出了以下特定目的：目标1。确定功效并定义2种新型同工型特异性PI3K抑制剂可能会影响T-ALL发病机理的作用机制。这将通过评估这些抑制剂在PTEN NULL T-ALL，人类T-ALL细胞系和主要患者样品中的动物模型中的影响来实现。重点将放在询问下游途径，以使用生化和遗传方法的组合来调节细胞周期进程，蛋白质合成和细胞存活。目的2。揭示可能导致次级电阻的潜在依赖PI3K依赖性和独立机制。这包括使用药物结合的硅模型，化学诱导的诱变以及动物中药物诱导的耐药性疾病，鉴定使用抗性的点突变和替代信号传导途径。将进行生化和遗传分析，后者包括基因表达微阵列和基于阵列的比较基因组杂交。目标3。确定同工型特异性PI3K抑制剂对人T细胞的发育，周围扩张，存活和功能的影响。这将通过评估独特的人胸腺/CD34+干细胞异种移植模型中的药物作用来实现。