Discovery of New Targets and Pathways for T-ALL Therapy

T-ALL 治疗新靶点和途径的发现

• 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
• 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

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）占儿科患者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T-ALL的治疗通常对正常组织有毒性，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途径，以推动T-ALL个性化药物的进展。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，以开发更特异、毒性更低的治疗T-ALL的药物。这一目标将通过三个具体目标来实现。在目标1中，我们将在本项目最后一个资助期内开展的工作的基础上，确定不存在双等位基因TCR γ链缺失（ABD亚型）和PTEN缺失的高风险T-ALL中的致癌途径和治疗靶点。我们将进行BH 3-profilestrin，以特异性靶向抗凋亡途径，并测试mTOR抑制剂，以改善高危ABD亚组的治疗。在目标2中，我们将建立在我们令人兴奋的新的初步数据，以确定TYK 2途径依赖的机制，并分析T-ALL中的选择性途径抑制剂。我们最近发现 大多数人类T-ALL细胞的生长和存活依赖于TYK 2酪氨酸活性，在这个目标中，我们将详细研究这一途径，以开发特异性靶向T-ALL细胞的有效抑制剂。在目标3中，我们将在最后一个资助期内继续我们的发现，即LEF 1是T-ALL中的肿瘤抑制因子，以使用斑马鱼和primagraft T-ALL模型来定义LEF 1缺失导致T-ALL的机制。每一个这些施舍涉及许多机会，与该计划中的其他项目密切互动，最终目标是为患有T-ALL的儿童和成人带来新的靶向治疗。