TARGETED DRUG THERAPY FOR LGL LEUKEMIA

描述（由申请人提供）：本提案的广泛长期目标是设计更好的大颗粒淋巴细胞（LGL）白血病治疗方案。LGL白血病是一种与骨髓衰竭相关的克隆性淋巴增生性疾病，可导致贫血和/或中性粒细胞减少症。该提议的中心假设是激活的Ras依赖性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中是组成性活性的，并且用法尼基转移酶抑制剂（FTIs）抑制该信号通路诱导白血病细胞中的细胞凋亡（程序性细胞死亡）。本提案的总体目标是评估法尼基转移酶抑制剂tipifarnib（Zarnestra）用于治疗LGL白血病的靶向药物治疗的疗效。次要目标是通过进行与临床试验相关的实验室研究，了解治疗反应和治疗失败的机制。本试验将作为位于Cleveland Clinic（Cleveland，OH）的骨髓衰竭联盟的一项新举措进行。通过该联盟招募全国患者，将提高实现本提案目标的可行性。每个具体目标将测试治疗功效的假定机制，其还将提供对LGL白血病发病机制的见解：具体目标1：确定Ras/ERK信号传导途径是否有助于LGL细胞存活;具体目标2：定义白血病T细胞和NK细胞的克隆型群体，并确定对Zarnestra的凋亡敏感性是否与分子应答相关;具体目标3：确定NK受体表达失调是否有助于疾病的发病机制。特定目标1中的相关研究旨在确定Ras转导途径的抑制是否介导对Zarnestra的治疗反应。我们将测量治疗反应是否与法尼基转移酶活性、FT酶调节蛋白、ERK活性、由Ras和ERK控制的下游抗凋亡蛋白以及已知对LGL细胞存活重要的其他蛋白相关。具体目标2中提出的相关研究应使用精确的分子技术鉴定克隆群体，并包括开发预测性体外细胞凋亡试验。具体目标3中提出的相关研究将测量NK受体对骨髓抑制的影响。这些研究的结果将为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.