Discovery of New Targets and Pathways for T-ALL Therapy

T细胞急性淋巴细胞性白血病(T-ALL)，占儿科所有病例的10%至15% 患者，尤其常见于青少年，占所有成人病例的25%。尽管 在长期无事件生存方面的重大进展，目前对T-ALL的治疗通常对 正常组织，在相当一部分患者中产生严重的急性和延迟性后遗症。这个 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个体化治疗的进展。 一个重要的长期目标是找到编码新的靶点和分子途径的基因 开发治疗T-ALL的更特异和毒性更低的药物。这个目标一定会实现的 通过三个具体目标。在目标1中，我们将在上一个资助期开展的工作基础上再接再厉 该项目旨在确定高危T淋巴细胞的致癌途径和治疗靶点。 等位基因TCRy链缺失(ABD亚型)和PTEN缺失。我们将进行BH3盈利，以具体 靶向抗凋亡途径并测试mTOR抑制剂以改进高危ABD的治疗 子群。在目标2中，我们将根据我们令人兴奋的新的初步数据来确定 TYK2途径依赖性，分析T-ALL中选择性途径抑制物。我们最近发现 大多数人类T细胞的生长和生存依赖于TYK2的酪氨酸活性，在这个目标中 我们将详细研究这一途径，以开发出针对T-ALL细胞的有效抑制剂。在……里面 目标3，我们将在上一次资助期间继续我们的发现，LEF1是T- ALL是为了定义LEF1的缺失导致使用斑马鱼的T-ALL的机制 原始机T-All型号。这些施舍中的每一个都包含了许多与之密切互动的机会 该计划中的其他项目，最终目标是将新颖的靶向治疗引入床边 患有T-ALL的儿童和成人。 相关性(请参阅说明)： 儿童T细胞急性淋巴细胞白血病(T-ALL)强化治疗的进展 临床结果显著，但一线治疗在大约25%的儿童和 超过50%的成年人，在最初失败后，这些患者的预后非常差。在这项研究中 在这个项目中，我们将测试PI3K/AKT/mT0R轴的抑制剂和抗凋亡通路TYK2酪氨酸 因LEF1的缺失而中断的激酶和通路，以开发针对高危T-ALL的新的靶向治疗。

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.