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)占儿童患者所有病例的10%至15%，在青少年中尤其常见，占成人所有病例的25%。尽管在长期无事件生存方面取得了重大进展，但目前对T-ALL的治疗往往对正常组织有害，在相当一部分患者中产生严重的急性和延迟后遗症。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个性化药物的发展。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进行的工作的基础上，在没有双等位TCRy链缺失(ABD亚型)和PTEN丢失的高危T-ALL中确定致癌途径和治疗靶点。我们将进行BH3干预，专门针对抗凋亡途径，并测试mTOR抑制剂，以改善高危ABD亚群的治疗。在目标2中，我们将在我们令人兴奋的新的初步数据的基础上，确定TYK2通路依赖的机制，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，以开发针对T-ALL细胞的有效抑制剂。在目标3中，我们将利用斑马鱼和原始T-ALL模型，继续我们在上一个资助期间的发现，即LEF1是T-ALL中的肿瘤抑制因子，以确定LEF1缺失导致T-ALL的机制。每一个ALM都包括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颖的有针对性的治疗方法。

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.