Farnesyltransferase Inhibitor Therapy for Myelodysplasia

描述(申请人提供)：骨髓增生异常综合征患者 (MDS)患有严重感染或出血，并经常因此而死亡 严重的全血细胞减少，有或没有进展为急性白血病。当前 MDS的治疗不会产生生存优势，任何形式的治疗都没有。 被证明具有足够的优势，足以被认为是标准的。突变的RAS 在大约20%-30%的MDS患者中发现了基因。 此外，在没有RAS突变的患者中，RAS仍然可能被激活 这是由于其他基因异常的影响而产生的。现在大家都知道 即使是突变的RAS也要活跃，它必须从 细胞质到质膜的一个过程，在这个过程中添加一个法尼基 由法尼基转移酶(FTase)组成的组起着重要的作用。 最近，作为FTase抑制剂并因此干扰的新化合物 随着RAS的激活已经被开发出来。该项目的目标将是 一种新型FTase抑制剂(R115777)在MDS中的首次临床研究 并确定生物反应和临床反应的最佳剂量。 (R115777可从癌症治疗和评估计划获得 国家癌症研究所。)我们的假设是，患者最有可能 响应者是那些具有可下调的基线RAS激活的人 在用FTase抑制剂治疗后。我们将从第一阶段开始 剂量发现研究。初步试验的目标将是确定 患者对R115777的耐受性，并估计最佳生物剂量。这些 然后将扩大试验范围，以确定患者中最多的 有可能表现出生物学和临床反应。阿司匹林的最佳剂量及其子集 对R115777有生物学反应的患者将通过测量 R115777和R115777给药剂量与血药浓度的关系 对生物终点的影响：FTase活性、RAS和Lamin B法尼化， 和RAS的下游效应物(MAP激酶和IL-1(后者基于我们的 最近的研究结果表明，RAS激活导致自分泌IL-1 白血病的生产))。总而言之，这项工作将确定 R115777，既可耐受，又能最大限度地发挥该分子对 FTASE/RAS系统。然后，该剂量将用于确定R115777是否 在治疗MDS方面有效，如果某些分子/生物标志物 反应的预测性。这些研究也将加深我们对 抑制法尼化作用与下游效应的关系 效应器和MDS中的抗肿瘤活性，应该作为一种范例有用 用于其他FTase抑制剂的临床应用。

DESCRIPTION (Provided by applicant): Patients with myelodysplastic syndrome (MDS) suffer from, and often succumb to, serious infections or bleeding because of severe pancytopenia, with or without progression to acute leukemia. Current therapy for MDS does not yield a survival advantage, and no form of therapy has proven advantageous enough to warrant being considered standard. Mutated RAS genes are found in about 20 percent-30 percent of patients with MDS. Furthermore, in patients without RAS mutations, Ras may still be activated indirectly because of the effects of other genetic aberrations. It is now known that in order for even mutated Ras to be active, it must move from the cytoplasm to the plasma membrane, a process in which the addition of a farnesyl group by the farnesyltransferase enzyme (FTase) plays an important role. Recently, novel compounds which act as FTase inhibitors and hence interfere with Ras activation have been developed. The goal of this project will be to perform the first clinical study of a novel FTase inhibitor (R115777) in MDS patients and to ascertain the optimum dose for biologic and clinical response. (R115777 is available from the Cancer Therapy and Evaluation Program of the National Cancer Institute.) Our hypothesis is that the patients most likely to respond are those who have baseline Ras activation which can be downregulated after treatment with an FTase inhibitor. We will start with a Phase I dose-finding study. The objective of the initial trial will be to ascertain patient tolerance to R115777, and to estimate optimum biologic dose. These trials will then be expanded to determine subsets of patients who are most likely to show biologic and clinical response. The optimum dose and subsets of patients with biologic response to R115777 will be ascertained by measuring the relationship between administered dose and plasma concentration of R115777 and effects on biologic endpoints: FTase activity, Ras and lamin B farnesylation, and downstream effectors of Ras (MAP kinase and IL-1 (the latter based on our recent results demonstrating that Ras activation leads to autocrine IL-1 production in leukemia)). In summary, this work will determine a dose of R115777 which is both tolerable and maximizes the impact of this molecule on the FTase/Ras system. This dose will then be used to determine if R115777 is effective in the treatment of MDS and if certain molecular/biologic markers are predictive of response. These studies will also enhance our understanding of the relationship between inhibition of farnesylation, effects on downstream effectors, and antitumor activity in MDS, and should be useful as a paradigm for the clinical application of other FTase inhibitors.