TARGETED DRUG THERAPY FOR LGL LEUKEMIA

描述(由申请人提供)：这项建议的广泛、长期目标是设计更好的治疗大颗粒淋巴细胞(LGL)白血病的方法。LGL白血病是一种克隆性淋巴增生性疾病，与骨髓衰竭有关，导致贫血和/或中性粒细胞减少。这一建议的中心假设是激活的RAS依赖的抗凋亡途径驱动白血病LGL的存活。我们还假设，NK受体表达失调导致了淋巴细胞介导的骨髓衰竭。我们发现，RAS/ERK通路在白血病LGL中是结构性激活的，用法尼斯利转移酶抑制剂(FTI)抑制这一信号通路可诱导白血病细胞的凋亡(细胞程序性死亡)。这项建议的总体目标是评估使用法尼基转移酶抑制剂替普法尼(Zarnestra)进行靶向药物治疗LGL白血病的疗效。第二个目标是通过与临床试验相关的实验室研究来了解治疗反应和治疗失败的机制。这项试验将作为总部设在俄亥俄州克利夫兰诊所的骨髓衰竭联盟的一项新倡议进行。通过该联盟在全国范围内招募患者，将增强实现这项建议中目标的可行性。每个特定目标将测试一个假定的治疗疗效机制，这也将为LGL白血病的发病机制提供洞察力：特定目标1：确定RAS/ERK信号通路是否有助于LGL细胞的存活；特定目标2：确定白血病T细胞和NK细胞的克隆型群体，并确定Zarnestra对凋亡的敏感性是否与分子反应相关；特定目标3：确定NK受体表达异常是否有助于疾病发病。特定目的1的相关研究旨在确定抑制RAS转导通路是否介导对Zarnestra的治疗反应。我们将测量治疗反应是否与Far-ysl转移酶活性、FTase调节的蛋白、ERK活性、由Ras和ERK控制的下游抗凋亡蛋白以及其他已知对LGL细胞生存重要的蛋白质相关。在特定目标2中提出的相关研究应该使用精确的分子技术来鉴定克隆群体，并包括开发一种体外预测细胞凋亡的方法。在特殊目的3中提出的相关研究将测量NK受体在骨髓抑制中的作用。这些研究的结果应该为治疗骨髓衰竭综合征的药物开发确定重要的分子靶点。

DESCRIPTION (provided by applicant): The broad, long-term goal of this proposal is to design better treatment for large granular lymphocyte (LGL) leukemia. LGL leukemia is a clonal lymphoproliferative disorder associated with bone marrow failure that results in anemia and/or neutropenia. The central hypothesis of this proposal is that an activated Ras-dependent anti-apoptotic pathway drives the survival of leukemic LGLs. We also hypothesize that dysregulated NK receptor expression contributes to lymphocyte-mediated bone marrow failure. We found that a Ras/ERK pathway is constitutively active in leukemic LGLs and that inhibition of this signaling pathway with farnyslytransferase inhibitors (FTIs) induces apoptosis (programmed cell death) in the leukemic cells. The overall goal of this proposal is to assess the therapeutic efficacy of targeted drug therapy with the farneslytransferase inhibitor tipifarnib (Zarnestra) for the treatment of LGL leukemia. The secondary goal is to understand the mechanism of treatment responses and treatment failures by pursuing correlative laboratory studies associated with a clinical trial. This trial will be conducted as a new initiative of the Bone Marrow Failures Consortium based at the Cleveland Clinic, Cleveland, OH. The feasibility of accomplishing the goals in this proposal will be enhanced by national patient recruitment through this Consortium. Each specific aim will test a postulated mechanism of treatment efficacy that will also provide insights into the mechanism of pathogenesis of LGL leukemia: Specific Aim 1: to determine whether a Ras/ERK signaling pathway contributes to LGL cell survival; Specific Aim 2: to define the clonotypic population of leukemic T cells and NK cells and determine whether apoptosis sensitivity to Zarnestra correlates with a molecular response; Specific Aim 3: to determine whether dysregulated NK receptor expression contributes to disease pathogenesis. Correlative studies in Specific Aim 1 are designed to determine whether inhibition of the Ras transduction pathway mediates treatment responses to Zarnestra. We will measure whether treatment responses are correlated to farnysltransferase activity, FTase-regulated proteins, ERK activity, downstream anti-apoptotic proteins controlled by Ras and ERK, and other proteins known to be important for LGL cell survival. Correlative studies proposed in Specific Aim 2 should identify the clonal population using precise molecular techniques and include the development of a predictive in vitro apoptotic assay. Correlative studies proposed in Specific Aim 3 will measure the effect of NK receptors on bone marrow suppression. Results of these studies should identify important molecular targets for drug development in bone marrow failure syndromes.