Molecular pathways and targeted therapies in human leukemia

人类白血病的分子途径和靶向治疗

• 批准号: 10224720
• 负责人: Adolfo A. Ferrando
• 金额: $ 96万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224720
• 关键词: Acute T Cell Leukemia; Bypass; Cell Proliferation; Cellular Metabolic Process; Chemoresistance; Clinic; Development; Disease; Disease Progression; Disease Resistance; Disease model; Enhancers; Epigenetic Process; Genetic; Genetic Transcription; Hematologic Neoplasms; High Prevalence; Human; Leukemic Cell; Malignant - descriptor; Mediating; Metabolic; Molecular; Mutation; NOTCH1 gene; Oncogenic; Pathway interactions; Patients; Proto-Oncogene Proteins c-akt; Public Health; Relapse; Research; Role; Signal Transduction; antileukemic agent; cell growth; interest; leukemia; new therapeutic target; novel; pre-clinical; programs; targeted treatment; therapeutic target; treatment response; tumor microenvironment

PROJECT SUMMARY T-lineage acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer in which novel more effective antileukemic drugs are needed for the treatment of patients with chemotherapy resistant disease. In this context the identification of activating mutations of NOTCH1 in over 60% of T-ALL has brought great interest to the development of targeted anti- NOTCH1 therapies in the treatment of this disease. However, early efforts to target NOTCH1 in the clinic have been hampered by limited antitumor activity. We have demonstrated that NOTCH1 is a critical regulator of cell growth and proliferation and identified MYC, the PI3K-AKT pathway and leukemia cell metabolism as critical effectors of the oncogenic program downstream of NOTCH1. Our central hypothesis is that leukemia persistence, disease progression and relapse are driven by signaling, genetic, epigenetic and metabolic circuits that bypass the antileukemic effects of NOTCH1 signaling. Here we will: (i) dissect molecular mechanisms wiring NOTCH1 with oncogenic transcriptional programs; (ii) functionally analyze the role of long-range enhancers in NOTCH1-induced transformation; (iii) explore the role of tumor microenvironment signals, metabolic and epigenetic plasticity as determinants of the therapeutic response to anti-NOTCH1 therapies and (iv) identify and functionally characterize new drug targets and antileukemic drugs synergistic with NOTCH inhibition for the treatment of T-ALL.

项目概要 T 系急性淋巴细胞白血病 (T-ALL) 是一种侵袭性血液癌症，其中 需要新的更有效的抗白血病药物来治疗患有白血病的患者 化疗耐药性疾病。在这种情况下，激活突变的鉴定 超过 60% 的 T-ALL 中存在 NOTCH1，这引起了人们对靶向抗 T-ALL 的开发产生了极大的兴趣。 NOTCH1疗法用于治疗这种疾病。然而，针对 NOTCH1 的早期努力 该诊所因抗肿瘤活性有限而受到阻碍。我们已经证明了 NOTCH1 是细胞生长和增殖的关键调节因子，并被鉴定为 MYC（PI3K-AKT） 途径和白血病细胞代谢作为致癌程序的关键效应器 NOTCH1 的下游。我们的中心假设是白血病持续存在，疾病 进展和复发是由信号、遗传、表观遗传和代谢回路驱动的 绕过 NOTCH1 信号传导的抗白血病作用。在这里我们将：（i）剖析分子 NOTCH1与致癌转录程序的连接机制； (ii) 功能分析 长程增强子在 NOTCH1 诱导的转化中的作用； (iii) 探索的作用 肿瘤微环境信号、代谢和表观遗传可塑性作为肿瘤的决定因素 对抗 NOTCH1 疗法的治疗反应以及 (iv) 识别和功能表征 新药靶点和抗白血病药物与NOTCH抑制协同治疗 高的。

项目成果

The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma.

• DOI: 10.1038/s41467-023-36713-8
• 发表时间: 2023-03-10
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Morgado-Palacin, Lucia;Brown, Jessie A.;Martinez, Thomas F.;Garcia-Pedrero, Juana M.;Forouhar, Farhad;Quinn, S. Aidan;Reglero, Clara;Vaughan, Joan;Heydary, Yasamin Hajy;Donaldson, Cynthia;Rodriguez-Perales, Sandra;Allonca, Eva;Granda-Diaz, Rocio;Fernandez, Agustin F.;Fraga, Mario F.;Kim, Arianna L.;Santos-Juanes, Jorge;Owens, David M.;Rodrigo, Juan P.;Saghatelian, Alan;Ferrando, Adolfo A.
• 通讯作者: Ferrando, Adolfo A.

Deregulation of enhancer structure, function, and dynamics in acute lymphoblastic leukemia.

• DOI: 10.1016/j.it.2021.03.005
• 发表时间: 2021-05
• 期刊: Trends in immunology
• 影响因子: 16.8
• 作者: Belver L;Albero R;Ferrando AA
• 通讯作者: Ferrando AA

Can one target T-cell ALL?

• DOI: 10.1016/j.beha.2018.10.001
• 发表时间: 2018-12
• 期刊: Best practice & research. Clinical haematology
• 作者: Ferrando A

Modeling NOTCH1 driven T-cell Acute Lymphoblastic Leukemia in Mice.

在小鼠中模拟 NOTCH1 驱动的 T 细胞急性淋巴细胞白血病。

• DOI: 10.21769/bioprotoc.3620
• 发表时间: 2020
• 期刊: Bio-protocol
• 影响因子: 0.8
• 作者: Wendorff,AgnieszkaA;Ferrando,AdolfoA
• 通讯作者: Ferrando,AdolfoA

Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies.

• DOI: 10.1038/s41467-022-28682-1
• 发表时间: 2022-02-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Cordo' V;Meijer MT;Hagelaar R;de Goeij-de Haas RR;Poort VM;Henneman AA;Piersma SR;Pham TV;Oshima K;Ferrando AA;Zaman GJR;Jimenez CR;Meijerink JPP
• 通讯作者: Meijerink JPP