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：
8550035
负责人：
A. THOMAS LOOK
金额：
$ 35.63万
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 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8550035
关键词：
Accounting Acute Acute T Cell Leukemia Adult Apoptotic Biological Assay Biological Models Cell Line Cells Child Childhood Clinical Collaborations DNA DNA Sequence Rearrangement 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 Medicine 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 Therapeutic Thymocyte Development Tumor Suppressor Proteins Tyrosine Universities Up-Regulation Work Zebrafish chemotherapy clinical application high risk human FRAP1 protein improved inhibitor/antagonist knock-down leukemia lymphoblast mTOR Inhibitor medical schools novel outcome forecast programs small hairpin RNA small molecule therapeutic target thymocyte

项目摘要

T-cell acute lynnphoblastic 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 blallelic 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. RELEVANCE (See instmctions): The intensification of therapy for children with T-cell acute lymphoblastic leukemia (T-ALL) has improved clinical outcomes substantially, but first-line therapy continues to fail in approximately 25% of children and in more than 50% of adults, and after initial failure these patients have a very poor prognosis. In this research project, we will test inhibitors of the PI3K/AKT/mT0R axis and anti-apoptotic pathways, the TYK2 tyrosine kinase and pathways disrupted by the loss of LEF1 to develop new targeted therapies for high risk T-ALL.

T 细胞急性淋巴细胞白血病 (T-ALL)，占儿科 ALL 病例的 10% 至 15% 患者中尤其常见，占成人 ALL 病例的 25%。尽管尽管在长期无事件生存方面取得了显着进展，但目前 T-ALL 的治疗通常对患者有毒性。正常组织，在相当一部分患者中产生严重的急性和迟发性后遗症。这这项研究的中心假设是对多步骤途径的深入了解需要分子发病机制来推动 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的基因和分子途径开发治疗 T-ALL 的特异性更强、毒性更小的药物。这个目标将会实现通过三个具体目标。在目标 1 中，我们将以上一个资助期间开展的工作为基础该项目旨在确定高风险 T-ALL 的致癌途径和治疗靶点，但缺乏等位基因 TCRy 链缺失（ABD 亚型）和 PTEN 丢失。我们将专门进行 BH3 分析靶向抗凋亡途径并测试 mTOR 抑制剂以改善高风险 ABD 的治疗子组。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 依赖 TYK2 酪氨酸活性来生长和生存，并且在此目标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。目标 3，我们将在最后一个资助期内继续我们的发现，即 LEF1 是 T-中的肿瘤抑制因子使用斑马鱼和 ALL 来定义 LEF1 丢失导致 T-ALL 的机制 primaraft T-ALL 型号。每一项施舍都涉及大量与人密切互动的机会该计划中的其他项目，最终目标是将新颖的靶向疗法带到床边患有 T-ALL 的儿童和成人。相关性（参见说明）： T细胞急性淋巴细胞白血病（T-ALL）儿童的强化治疗有所改善临床结果显着，但一线治疗在大约 25% 的儿童和超过 50% 的成年人，在最初的失败后，这些患者的预后非常差。在这项研究中项目中，我们将测试 PI3K/AKT/mT0R 轴和抗凋亡途径的抑制剂 TYK2 酪氨酸研究人员利用因 LEF1 缺失而中断的激酶和通路来开发针对高风险 T-ALL 的新靶向疗法。