Novel therapeutics of targeting mTOR pathway in T-cell leukemia

T细胞白血病靶向mTOR通路的新疗法

• 批准号: 9108936
• 负责人: Fukun Guo
• 金额: $ 20.36万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-10 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108936
• 关键词: Acute T Cell Leukemia; Apoptosis; Ara-C; Biology; CCI-779; Cell Death; Cell Line; Cell Survival; Cells; Cellular Metabolic Process; Clinic; Clinical; Complex; Cytarabine; DNA Damage; DNA Repair; DNA Repair Pathway; Disease remission; Drug resistance; Drug-sensitive; Effectiveness; FRAP1 gene; Fanconi Anemia pathway; Fanconi' s Anemia; Generations; Growth; Harvest; Human; Immature T-Lymphocyte; In Vitro; Investigation; Length; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Modeling; Molecular; Mus; Nuclear; Nutrient; Oranges; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Principal Investigator; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Recurrent disease; Relapse; Reporting; Research; Resistance; Sampling; Signal Pathway; Signal Transduction; Sirolimus; Stimulus; Survival Rate; T-Cell Leukemia; Testing; Therapeutic; Therapeutic Effect; Translations; Validation; Work; Xenograft procedure; analog; cancer type; cell growth; chemotherapy; effective therapy; extracellular; in vivo; inhibitor/antagonist; innovation; new therapeutic target; novel; outcome forecast; overexpression; progenitor; public health relevance; response; sensor; tumor; tumorigenesis

 DESCRIPTION (provided by applicant): Drug resistance/disease relapse in the majority of T-cell acute lymphoblastic leukemia (T-ALL) patients demands better understanding T-ALL biology that may help develop more effective therapy. Mammalian target of rapamycin (mTOR), present in two cellular complexes: mTORC1 and mTORC2, has been related to tumorigenesis and/or drug resistance in several cancers. Targeting mTORC1 by rapamycin analogs has been tried in various tumor clinical contexts. However, the length of patient response is limited and not all patients respond. To overcome these limitations, the second generation of mTOR inhibitors have been developed to target both mTORC1 and mTORC2. This project is motivated by our new finding that mTOR functions upstream of FANCD2 of the Fanconi anemia DNA repair pathway to regulate DNA damage response (DDR) in T-ALL cells. The proposed studies focus on testing the novel hypothesis that mTOR-regulated DDR constitutes an important drug resistance machinery in drug-resistant/relapsed T-ALL, and targeting this pathway increases effectiveness of DNA damaging chemotherapy. The research will examine whether a mTOR-FANCD2-ATR-Chk1/ATM-Chk2 DDR signaling node exists and is hyper-activated in drug- resistant/relapsed T-ALL (Aim 1). The research will further determine whether targeting mTOR-regulated DDR pathway using dual mTORC1/mTORC2 inhibitor combined with DNA damaging drug overcomes drug resistance in mice xenografted with drug-resistant/relapsed primary T-ALL patient cells (Aim 2). Successful execution of the project will not only help us in innovating our understanding of drug resistance in T-ALL therapy, but also allow a long sought-after DNA damage sensitization therapeutic principle to tackle drug resistant T-ALL.

 描述（由适用提供）：大多数T细胞急性淋巴细胞白血病（T-ALL）患者的耐药性/疾病继电器要求更好地了解T-ALL生物学，这可能有助于开发更有效的治疗。雷帕霉素的哺乳动物靶标（MTOR）存在于两个细胞复合物中：mTORC1和MTORC2，与几种癌症的肿瘤发生和/或耐药性有关。在各种肿瘤临床环境中，尝试了雷帕霉素类似物的MTORC1。但是，患者反应的长度有限，并非所有患者反应。为了克服这些局限性，已经开发了第二代MTOR抑制剂来靶向MTORC1和MTORC2。我们的新发现激发了该项目，即Fanconi贫血DNA修复途径的FANCD2上游功能以调节T-ALL细胞中DNA损伤响应（DDR）。拟议的研究重点是检验新的假设，即MTOR调节的DDR构成了耐药/复发的T-ALL中重要的耐药性机制，并且针对该途径提高了DNA损伤化疗的有效性。该研究将检查MTOR-FANCD2-ATR-CHK1/ATM-CHK2 DDR信号节点是否存在，并且在耐药/复发的T-ALL中过度激活（AIM 1）。这项研究将进一步确定使用双MTORC1/MTORC2抑制剂联合使用DNA损伤药物在用耐药/耐药/耐药的原发性T-ALL患者细胞异种移植的小鼠中靶向MTOR调节的DDR途径是否克服了耐药性（AIM 2）。该项目的成功执行不仅将帮助我们创新对T-All治疗中的耐药性的理解，而且还允许长时间的SCART DNA损伤敏感性理论原理来解决抗药性T-all。