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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：
8346060
负责人：
Thomas G Diacovo
金额：
$ 33.2万
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/8346060
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 Expression 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. PUBLIC HEALTH RELEVANCE: The work outlined in this proposal will not only improve our understanding of the mechanisms that contribute to the development and survival of T-ALL, but will also lead to a less toxic strategy to treat this devastating disease, especially in our most vulnerable population: children. )

描述（由申请人提供）：