Targeting non-classical oncogenes as therapy for T-ALL

针对非经典癌基因治疗 T-ALL

• 批准号: 8513283
• 负责人: Thomas G Diacovo
• 金额: $ 31.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/8513283
• 关键词: 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

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) 是一种侵袭性血液癌症，发生在儿童和成人中。尽管进行了强化治疗，25% 的儿童和青少年以及 50% 的 T-ALL 成人患者最终仍会死于该疾病。此外，癌症治疗的后期影响，包括永久性器官损伤、激素和生殖功能障碍以及继发性癌症，是儿童特别关注的问题，因为目前的治疗不加区别地针对所有分裂细胞。该提案的目标是确定并治疗针对 T-ALL 生长和生存所必需的途径，抑制该途径的毒性将比标准化疗低得多。据报道，I 类磷酸肌醇 3 激酶 (PI3K)/Akt 信号通路在超过 40% 的 T-ALL 病例中被激活。尽管四种不同的 I 类 PI3K 亚型可能参与 T-ALL 发病机制，但没有一个亚型参与这一过程。使用基因改造的动物和新型小分子抑制剂，我们已经鉴定出对于 T-ALL 的发展和生存至关重要的特定亚型。基于这些观察，我们提出可以利用这种血液恶性肿瘤对这些特定 PI3K 亚型的“成瘾”作为 T-ALL 的新治疗途径。为了实现这些目标，我们提出以下具体目标： 目标 1. 确定 2 种新型亚型特异性 PI3K 抑制剂可能影响 T-ALL 发病机制的功效并确定其作用机制。这将通过评估这些抑制剂在 PTEN 缺失 T-ALL 动物模型、人类 T-ALL 细胞系和主要患者样本中的效果来实现。重点将放在利用生化和遗传方法相结合来探究调节细胞周期进程、蛋白质合成和细胞存活的下游途径。目标 2. 揭示可能导致继发耐药的潜在 PI3K 依赖性和独立机制。这包括使用药物结合、化学诱导突变和动物药物诱导耐药性疾病的计算机模型来识别赋予抗性的点突变和替代信号通路。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. 确定异构体特异性 PI3K 抑制剂对人类 T 细胞的发育、外周扩张、存活和功能的影响。这将通过在独特的人类胸腺/CD34+干细胞异种移植模型中评估药物效应来实现。