Project 2 - Targeted Therapies for T-ALL.

项目摘要/摘要 该项目的长期目标是为T细胞急性淋巴母细胞瘤开发新的靶向治疗方法 白血病(T-ALL)。T-ALL是一种侵袭性的血液系统恶性肿瘤，占儿童ALL和 25%的成年人-全部。目前的治疗包括强烈的化疗，这种化疗与急性和 慢性威胁生命或使人虚弱的毒物。儿童的五年无病生存率为70%-75%，儿童为30%-40% 60岁以下的成年人，60岁以上的成年人不到10%。复发后预后很差，为3年。 无事件存活率仅为10-15%。有令人信服的证据表明，MYC活动的增加是 大多数T-ALL的发病机制。虽然myc是一种强有力的致癌基因，但它也有一个致命弱点。在……里面 除了提供增殖信号外，MYC还强烈地诱导细胞凋亡，部分是通过 ARF/MDM2/TP53通路。事实上，在没有额外的突变/信号来灭活细胞凋亡的情况下， MYC的表达不足以诱发白血病/淋巴瘤。在T-ALL中，这第二个信号很可能 CDKN2A编码p14(ARF)的纯合失活突变存在于约80%的T-ALL中。 总之，这些数据支持这样一种假设，即靶向MYC相关生存通路的药物 会选择性地对T-ALL细胞产生毒性。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的相互作用提供了一个关键 T-ALL细胞的生存信号。因此，我们推测CXCR4阻滞剂可能具有治疗活性 穿着T-All。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CXCR4的抑制非常敏感。提出了以下具体目标来测试这些目标 假设。 目的：1.检测BL-8040联合奈拉滨治疗成人复发性/难治性T细胞白血病的疗效。 ALL/淋巴母细胞性淋巴瘤。 目的2.开发新的治疗策略，针对T-ALL对MYC信号的依赖性。

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.