New Approaches to the Biology and Treatment of Myelodysplastic Syndromes (MDS)

描述(由申请人提供)：随着美国人口老龄化，骨髓增生异常综合征(MDS)的发病率可能会增加。然而，目前还没有令人满意的治疗方法。此外，标准的分类系统无法解释这些疾病的自然病史或治疗后结果的大部分变异性。这些问题反映了对MDS“生物学”知识的缺乏。最近出现了阐明MDS分子发病机制的新方法。该计划项目赠款(PPG)将具有临床、分子生物学和统计学专业知识的研究人员聚集在一起，以解决上述问题。PPG的主要目标是为低风险和高风险形式的MDS开发新的治疗方法。项目1将探索新的靶向疗法在治疗高危MDS中的作用，并评估NCI工作组最近颁布的新类别“轻微反应”与生存和生活质量的相关性。低风险MDS的治疗(项目5)将基于Molldrem博士的假设，即如果多肽过度表达破坏免疫耐受，来自正常组织蛋白的多肽可以成为细胞毒性T淋巴细胞(CTL)的自身抗原。提供了支持这一假设的初步数据，并表明用蛋白酶3衍生的表位接种可以诱导缓解。项目5尽管采取了疫苗接种策略，但仍出现高危MDS的患者将在项目1中接受治疗。这两个项目都将使用共同的方法来评估生活质量，并都采用针对实验室中可量化目标的治疗方法，从而激励对基于实验室的终点和临床结果之间的关系进行统计评估。PPG的第二个目标是进一步深入了解MDS的分子发病机制，尽管在10-25%的MDS患者中会发生Flt3(项目2)、RAS或PTPN11(核心B)或Hox基因过度表达(项目4)的激活突变，但随着疾病的发展，缺乏同时监测这些突变或试图发现新突变的大型人群研究(项目2)。例如，项目2、4和核心B之间的相互作用应该允许对Gillland-Griffin模型中隐含的假设进行评估，即虽然激活赋予生存优势的“1型”突变(例如，RAS.PTPN11、Flt3)将经常伴随阻止分化的“2型”异常(例如，Hox基因过度表达)，但两种1型突变不会在同一患者中发生。项目3将研究表观遗传现象在MDS发病/进展中所起的作用；多达30%的MDS患者具有超甲基化基因，但这种现象从未在激活突变或Hox过度表达的背景下进行过检验。PPG的第三个目标是提高提供准确预测的能力。为此，我们将检验这样一种假设，即基于实验室的项目(项目2-5)的结果将提供补充FAB、WHO或IPSS系统提供的信息的信息。例如，初步数据表明，一种名为rIL的基因高度甲基化会导致特别糟糕的预后。这些目标的实现将得益于每年在M.D.Anderson就诊的240名患者以及这些患者返回进行后续治疗的频率。

DESCRIPTION (provided by applicant): The incidence of myelodysplastic syndromes (MDS) is likely to increase as the U.S. population ages. Nonetheless, there are no satisfactory treatments. Furthermore, standard classification systems fail to explain much of the variability in either the natural history of these illnesses or their outcome after treatment. These problems reflect a lack of knowledge of the "biology" of MDS. New methods for clarifying the molecular pathogenesis of MDS have recently become available. This Program Project Grant (PPG) brings together investigators with clinical, molecular biological, and statistical expertise to address the problems noted above. The primary goal of the PPG is to develop new therapies for both low and high-risk forms of MDS. Project 1 will explore the role of new-targeted therapies in the treatment of high-risk MDS and assess the relevance to survival and quality of life of the new category "minor response" recently promulgated by an NCI Working Group. Therapy for low risk MDS (Project 5) will be based on Dr.Molldrem's hypothesis that peptides derived from normal tissue proteins can be autoantigens for cytotoxic T-lymphocytes (CTL) if peptide overexpression breaks immune tolerance. Preliminary data supporting this hypothesis and suggesting that vaccination with proteinase 3-derived epitopes can induce remissions are presented. Project 5 patients developing high-risk MDS despite the vaccination strategy will be treated on Project 1. Both Projects will use a common approach to evaluate quality-of-life and both employ therapies directed at targets that are quantifiable in the laboratory, thus motivating statistical evaluation of relationships between laboratory-based endpoints and clinical outcome. The PPG's second goal is gain further insight into the molecular pathogenesis of MDS Although activating mutations in FLT3(Project 2), RAS or PTPN11(Core B), or HOX gene overexpression (Project 4) occur in 10-25% of MDS patients, large population-based studies that simultaneously monitor these mutations, or attempt to uncover new ones(Project 2), as the disease evolves are lacking. Interactions between Projects 2, 4, and Core B should, for example, permit evaluation of the hypothesis implicit in the Gilliland-Griffin model that while activating "type 1" mutations that confer a survival advantage (e.g. RAS.PTPN11, FLT3) will regularly be accompanied by "type 2 "aberrations that block differentiation (e.g. HOX gene overexpression), two type 1 mutations will not occur in the same patient. The role played by epigenetic phenomena, e.g. hypermethylation, in MDS pathogenesis/progression will be examined in Project 3; up to 30% of MDS patients have hypermethylated genes, but this phenomenon has never been examined in the context of activating mutations or HOX overexpression. The PPG's third goal is to enhance the ability to provide accurate prognoses. To do this we will test the hypothesis that the findings from the laboratory-based projects (Projects 2- 5) will provide information that will complement the information provided by the FAB, WHO, or IPSS systems. Preliminary data for example suggests that hypermethylation of a gene known as Ril confers a particularly poor prognosis. Achievement of these goals will be facilitated by the 240 patients seen annually at M.D. Anderson and the frequency with which these patients return for follow-up.