Project 2 - Targeted Therapies for T-ALL.

项目 2 - T-ALL 的靶向治疗。

• 批准号: 10194401
• 负责人: GEOFFREY L UY
• 金额: $ 27.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-03 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194401
• 关键词: Acute; Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Address; Adult; Age; Allogenic; Apoptosis; BCL2 gene; BCL2L1 gene; BH3 Domain; Blood Circulation; Bypass; CDKN2A gene; CXCL12 gene; CXCR4 gene; Cell Cycle; Cell Death; Child; Childhood Acute Lymphocytic Leukemia; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Correlative Study; Data; Dependence; Disease; Disease-Free Survival; FBXW7 gene; Foundations; Gene Expression; Goals; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Lead; Life; Lymphoblastic lymphoma; MCL1 gene; MDM2 gene; Marrow; Mutation; NOTCH1 gene; Nelarabine; Oncogenes; PTEN gene; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phase; Prognosis; Publishing; Recovery; Refractory; Relapse; Resistance; Safety; Sampling; Signal Transduction; Specialized Program of Research Excellence; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Toxic effect; United States; Xenograft procedure; acute T-cell lymphoblastic leukemia cell; base; cell growth; chemokine receptor; chemotherapy; clinical development; hematopoietic cell transplantation; human model; in vivo; inhibitor/antagonist; leukemia; leukemia/lymphoma; new therapeutic target; novel; novel therapeutic intervention; peripheral blood; pre-clinical; preclinical study; protein expression; receptor; response; response biomarker; synthetic peptide; targeted agent; targeted treatment

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to develop novel targeted therapies for T-cell acute lymphoblastic leukemia (T-ALL). T-ALL is an aggressive hematologic malignancy that comprises 15% of pediatric ALL and 25% of adult-ALL. Current treatment consists of intense chemotherapy that is associated with acute and chronic life-threatening or debilitating toxicities. Five-year event-free survival is 70-75% for children, 30-40% for adults under 60, and less than 10% for adults over age 60. The prognosis after relapse is dismal, with 3 year event-free survival of only 10-15%. There is compelling evidence that increased MYC activity is central to the pathogenesis of most cases of T-ALL. Although MYC is a potent oncogene, it has an Achilles heel. In addition to providing a proliferative signal, MYC strongly induces apoptosis, in part, through an ARF/MDM2/TP53 pathway. Indeed, without additional mutations/signals which inactivate apoptosis, increased MYC expression is not sufficient to induce leukemia/lymphoma. In T-ALL, this second signal is likely homozygous inactivating mutations of CDKN2A encoding p14 (ARF), which are present in ~80% of T-ALL. Together, these data support the hypothesis that agents that target MYC-associated survival pathways will be selectively toxic to T-ALL cells. CXCR4 is by far the most highly expressed chemokine receptor expressed on T-ALL cells, and there is evidence that CXCL12, through interaction with CXCR4, provides a key survival signal for T-ALL cells. Thus, we hypothesize that CXCR4 blockade may have therapeutic activity in T-ALL. Consistent with this hypothesis, our preliminary and published preclinical data show that T-ALL cells are exquisitely sensitive to CXCR4 inhibition. The following specific aims are proposed to test these hypotheses. Aim 1. To test the combination of BL-8040 and nelarabine in adults with relapsed/refractory T- ALL/lymphoblastic lymphoma. Aim 2. To develop novel therapeutic strategies that target the dependence of T-ALL on MYC-signaling.

项目总结/摘要 该项目的长期目标是开发新的靶向治疗T细胞急性淋巴细胞白血病的方法。 白血病（T-ALL）。T-ALL是一种侵袭性恶性血液病，占儿童ALL的15%， 成人的25%。目前的治疗包括强烈的化疗， 慢性危及生命或使人衰弱的毒性。儿童的5年无事件生存率为70-75%， 60岁以下的成年人，60岁以上的成年人不到10%。复发后预后差， 无事件生存率仅为10- 15%。有令人信服的证据表明，增加多年期项目活动是 大多数T-ALL病例的发病机制。虽然MYC是一种有效的致癌基因，但它有一个致命弱点。在 除了提供增殖信号外，MYC还部分地通过诱导细胞凋亡来强烈诱导细胞凋亡。 ARF/MDM 2/TP 53通路。事实上，在没有抑制凋亡的额外突变/信号的情况下， MYC表达不足以诱导白血病/淋巴瘤。在T-ALL中，第二个信号可能是 CDKN 2A编码p14（ARF）的纯合失活突变，约80%的T-ALL中存在。 总之，这些数据支持这样的假设，即靶向MYC相关生存途径的药物 会选择性地对T-ALL细胞产生毒性。CXCR 4是迄今为止表达最高的趋化因子受体 有证据表明，CXCL 12通过与CXCR 4相互作用，提供了一个关键的， T-ALL细胞的存活信号。因此，我们假设CXCR 4阻断可能具有治疗活性， 在T-ALL中。与这一假设一致，我们的初步和已发表的临床前数据显示，T-ALL 细胞对CXCR 4抑制非常敏感。提出了以下具体目标来检验这些目标 假设 目标1.为了测试BL-8040和奈拉滨在复发性/难治性T-细胞癌成人患者中的组合， ALL/淋巴母细胞性淋巴瘤。 目标2.开发新的治疗策略，靶向T-ALL对MYC信号的依赖性。