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: 8710114
• 负责人: A. THOMAS LOOK
• 金额: $ 36.76万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8710114
• 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

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），占儿童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 长期无事件生存率的显著进步，目前的T-ALL治疗通常对 正常组织，在相当一部分患者中产生严重的急性和延迟后遗症。的 这项研究的中心假设是，深入了解多步途径， 分子发病机制的研究需要推动T-ALL个体化治疗的进展。 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， 开发更特异、毒性更低的药物治疗T-ALL。这一目标将得以实现 通过三个具体目标。在目标1方面，我们会以 该项目旨在确定缺乏以下因素的高风险T-ALL中的致癌途径和治疗靶点： blallelic TCR γ链缺失（ABD亚型）和PTEN缺失。我们将进行BH 3分析， 靶向抗凋亡途径，并测试mTOR抑制剂，以改善高危ABD的治疗 亚群在目标2中，我们将基于令人兴奋的新的初步数据来确定 TYK 2通路依赖性和分析T-ALL中的选择性通路抑制剂。我们最近发现 大多数人T-ALL的生长和存活依赖于TYK 2酪氨酸活性， 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，我们将在最后一个资助期间继续我们的发现，即LEF 1是T细胞中的肿瘤抑制因子， ALL来定义LEF 1缺失导致T-ALL的机制， primagraft T-ALL模型。这些施舍中的每一个都涉及许多与之密切互动的机会。 该计划中的其他项目，最终目标是将新的靶向治疗带到床边， 儿童和成人T-ALL。 相关性（见说明）： 儿童T细胞急性淋巴细胞白血病（T-ALL）的强化治疗有所改善 临床结果基本上，但一线治疗仍然失败，约25%的儿童和 超过50%的成年人，并且在初始失败后，这些患者的预后非常差。本研究 项目，我们将测试PI 3 K/AKT/mT 0 R轴和抗凋亡途径的抑制剂，TYK 2酪氨酸 激酶和途径的LEF 1的损失破坏，开发新的靶向治疗高危T-ALL。