Project 2 - Targeted Therapies for T-ALL.

项目 2 - T-ALL 的靶向治疗。

基本信息

批准号：
10439622
负责人：
GEOFFREY L UY
金额：
$ 32.9万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-03 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439622
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 antagonist base cell growth chemokine receptor chemotherapy clinical development hematopoietic cell transplantation human model in vivo inhibitor 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

项目摘要

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.

项目概要/摘要该项目的长期目标是开发针对T细胞急性淋巴细胞白血病的新型靶向疗法白血病（T-ALL）。 T-ALL 是一种侵袭性血液恶性肿瘤，占儿童 ALL 的 15% 成人 ALL 的 25%。目前的治疗包括与急性和慢性疾病相关的强烈化疗。慢性危及生命或使人衰弱的毒性。儿童的五年无事件生存率为 70-75%，儿童的五年无事件生存率为 30-40% 60岁以下成人，60岁以上成人不足10%。复发后预后较差，3年无事件生存率仅为 10-15%。有令人信服的证据表明，增加 MYC 活性对于大多数 T-ALL 病例的发病机制。尽管 MYC 是一种强效致癌基因，但它也有一个致命弱点。在除了提供增殖信号外，MYC 还部分通过以下方式强烈诱导细胞凋亡： ARF/MDM2/TP53 通路。事实上，如果没有额外的突变/信号来灭活细胞凋亡，增加 MYC 表达不足以诱发白血病/淋巴瘤。在 T-ALL 中，第二个信号可能是编码 p14 (ARF) 的 CDKN2A 纯合失活突变，存在于约 80% 的 T-ALL 中。总之，这些数据支持这样的假设：靶向 MYC 相关生存途径的药物对 T-ALL 细胞具有选择性毒性。 CXCR4 是迄今为止表达最高的趋化因子受体在 T-ALL 细胞上表达，有证据表明 CXCL12 通过与 CXCR4 相互作用，提供了一个关键的 T-ALL 细胞的生存信号。因此，我们假设 CXCR4 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表明，T-ALL 细胞对 CXCR4 抑制极其敏感。提出以下具体目标来测试这些假设。目标 1. 测试 BL-8040 和奈拉滨联合治疗成人复发/难治性 T- ALL/淋巴母细胞淋巴瘤。目标 2. 针对 T-ALL 对 MYC 信号传导的依赖性，开发新的治疗策略。