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) 占儿童患者 ALL 病例的 10% 至 15%，在青少年中尤其常见，占成人 ALL 病例的 25%。尽管在长期无事件生存方面取得了重大进展，但目前的 T-ALL 治疗通常对正常组织具有毒性，在相当一部分患者中产生严重的急性和迟发性后遗症。这项研究的中心假设是，需要深入了解分子发病机制的多步骤途径，以推动 T-ALL 个性化医疗的进展。一个重要的长期目标是找到编码新靶点和分子途径的基因，以开发用于治疗 T-ALL 的特异性更强、毒性更小的药物。这一目标将通过三个具体目标来实现。在目标 1 中，我们将在该项目最后一个资助期间开展的工作的基础上确定不存在双等位基因 TCRy 链缺失（ABD 亚型）和 PTEN 丢失的高风险 T-ALL 的致癌途径和治疗靶点。我们将进行 BH3 增强以专门针对抗凋亡途径，并测试 mTOR 抑制剂以改善高风险 ABD 亚组的治疗。在目标 2 中，我们将基于令人兴奋的新初步数据来确定 TYK2 通路依赖性机制并分析 T-ALL 中的选择性通路抑制剂。我们最近发现大多数人类 T-ALL 的生长和生存依赖于 TYK2 酪氨酸活性，为此，我们将详细研究该通路，以开发专门针对 T-ALL 细胞的有效抑制剂。在目标 3 中，我们将在上一个资助期间继续研究 LEF1 是 T-ALL 中的肿瘤抑制因子的发现，以使用斑马鱼和原代移植 T-ALL 模型来定义 LEF1 缺失导致 T-ALL 的机制。每一项救助都涉及与该计划中其他项目密切互动的大量机会，最终目标是为患有 T-ALL 的儿童和成人带来新颖的靶向疗法。