Discovery of New Targets and Pathways for T-ALL Therapy

T-ALL 治疗新靶点和途径的发现

基本信息

批准号：
8901763
负责人：
A. THOMAS LOOK
金额：
$ 37.9万
依托单位：
DANA-FARBER CANCER INST
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：
2012-09-24 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8901763
关键词：
Accounting Acute Acute Lymphocytic Leukemia Acute T Cell Leukemia Adult Apoptotic Biological Assay Biological Models Cell Line Cells Child Childhood Clinical Collaborations DNA Data Dependence Detection Development Diagnosis Disease remission Disease-Free Survival Exhibits Failure Funding Genes Genetic Genotype Goals Gray unit of radiation dose Growth Health Sciences Human Image Knowledge Mediating Modeling Molecular Molecular Target Mus Normal tissue morphology Oncogenic Oregon Outcome PI3K/AKT PTEN gene Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Protein Tyrosine Kinase Proto-Oncogene Proteins c-akt Relapse Repression Research Research Project Grants Resistance Role Sampling Staging Subgroup Synthesis Chemistry T-Lymphocyte T-Lymphocyte Subsets TYK2 Teenagers Testing Thymocyte Development Tumor Suppressor Proteins Tyrosine Universities Up-Regulation Work Zebrafish chemotherapy clinical application high risk human FRAP1 protein improved inhibitor/antagonist knock-down lymphoblast mTOR Inhibitor medical schools novel outcome forecast pediatric patients personalized medicine programs small hairpin RNA small molecule targeted treatment therapeutic target therapy resistant thymocyte

项目摘要

T-cell acute lymphoblastic leukemia (T-ALL), which comprises 10% to 15% of ALL cases in pediatric patients, is especially common in teenagers and accounts for 25% of ALL cases in adults. Despite significant advances in long-term event-free survival, current treatments for T-ALL are often toxic to normal tissues, producing serious acute and delayed sequelae in a substantial fraction of patients. The central hypothesis for this research is that in-depth knowledge of multi-step pathways of molecular pathogenesis is needed to propel progress toward personalized medicine for T-ALL. An important long-term goal is to find genes encoding new targets and molecular pathways for the development of more specific and less toxic drugs for the treatment of T-ALL. This goal will be achieved through three specific aims. In Aim 1, we will build on work conducted during the last funding period of this project to identify oncogenic pathways and therapeutic targets in high risk T-ALLs with the absence of biallelic TCRy chain deletions (ABD subtype) and PTEN loss. We will conduct BH3-profillng to specifically target anti-apoptotic pathways and also test mTOR inhibitors to improve therapy for the high risk ABD subgroup. In Aim 2, we will build on our exciting new preliminary data to determine the mechanisms of TYK2 pathway dependence and analyze selective pathway inhibitors in T-ALL. We recently discovered that the majority of human T-ALLs depend on TYK2 tyrosine activity for growth an survival, and In this Aim we will interrogate this pathway in detail to develop potent inhibitors that specifically target T-ALL cells. In Aim 3, we will pursue our discovery during the last funding period that LEF1 Is a tumor suppressor in T-ALL to define the mechanisms through which loss of LEF1 contributes to T-ALL using zebrafish and primagraft T-ALL models. Each of these Alms involves numerous opportunities to interact closely with other projects in this program, with the ultimate goal of bringing novel targeted therapies to the bedside for children and adults with T-ALL.

T细胞急性淋巴细胞白血病（T-ALL）占小儿患者所有病例的10％至15％，在青少年中尤为常见，占成年人所有病例的25％。尽管长期无事件生存率取得了重大进展，但当前的T-All治疗方法通常对正常组织有毒，在很大一部分患者中产生了严重的急性和延迟后遗症。这项研究的中心假设是，需要深入了解分子发病机理的多步途径，以推动朝着个性化的T-all进展。一个重要的长期目标是找到编码新靶标的基因和分子途径，以开发更特异性和毒性的药物来治疗T-all。这个目标将通过三个特定目标实现。在AIM 1中，我们将基于该项目的最后一项资金期间进行的工作，以识别高风险T-alls中的致癌途径和治疗靶标，并且没有双重TCRY链缺失（ABD子类型）和PTEN损失。我们将进行BH3-螺纹填充，以特别针对抗凋亡途径，并测试MTOR抑制剂，以改善对高风险ABD亚组的治疗。在AIM 2中，我们将基于令人兴奋的新初步数据，以确定TYK2途径依赖性的机制，并分析T-ALL中的选择性途径抑制剂。我们最近发现大多数人的T型均取决于Tyk2酪氨酸活性来生长生存，并且在此目的中，我们将详细询问该途径，以开发出有效靶向T-All细胞的有效抑制剂。在AIM 3中，我们将在最后一个资金期间追求我们的发现，即LEF1是T-All中的肿瘤抑制器，以定义LEF1的损失使用斑马鱼和Primagraft T-All模型有助于T-All的机制。这些施舍中的每一个都涉及许多机会与该计划中的其他项目紧密互动，其最终目标是将新颖的目标疗法带到T-All的儿童和成人的床边。