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

骨髓增生异常综合征 (MDS) 的生物学和治疗新方法

• 批准号: 6907648
• 负责人: ELIHU ESTEY
• 金额: $ 196.03万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-21 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6907648
• 关键词: clinical research

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.

描述（由申请人提供）：骨髓增生异常综合征（MDS）的发病率可能会随着美国人口的老龄化而增加。然而，没有令人满意的治疗方法。此外，标准分类系统无法解释这些疾病的自然史或治疗后结果的大部分变异性。这些问题反映了对MDS的“生物学”知识的缺乏。阐明MDS的分子发病机制的新方法最近已经成为可用的。该计划项目资助（PPG）汇集了具有临床，分子生物学和统计学专业知识的研究人员，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开发新疗法。项目1将探讨新靶向治疗在高危MDS治疗中的作用，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，即如果肽过表达破坏免疫耐受，则源自正常组织蛋白的肽可以是细胞毒性T淋巴细胞（CTL）的自身抗原。初步的数据支持这一假设，并表明与蛋白酶3衍生的表位接种疫苗可以诱导缓解。项目5中，尽管采用了疫苗接种策略，但仍发生高危MDS的患者将在项目1中接受治疗。这两个项目将使用一种共同的方法来评估生活质量，并且都采用针对实验室可量化目标的治疗，从而促进对基于实验室的终点与临床结局之间关系的统计评估。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10-25%的MDS患者发生FLT 3（项目2）、RAS或PTPN 11（核心B）或HOX基因过表达的激活突变（项目4），但缺乏同时监测这些突变或随着疾病进展尝试发现新突变（项目2）的大型基于人群的研究。例如，项目2、4和核心B之间的相互作用应该允许评估Gilliland-Griffin模型中隐含的假设，即在激活赋予生存优势的“1型”突变的同时，（例如RAS.PTPN11、FLT 3）将经常伴随阻断分化的“2型“畸变。如果两种类型的突变（例如HOX基因过表达），则两种类型的1型突变不会在同一患者中发生。表观遗传现象（如超甲基化）在MDS发病/进展中所起的作用将在项目3中进行研究;高达30%的MDS患者具有超甲基化基因，但从未在激活突变或HOX过表达的背景下研究过这种现象。PPG的第三个目标是增强提供准确诊断的能力。为此，我们将检验以下假设：实验室项目（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，一种被称为Ril的基因的超甲基化赋予了特别差的预后。这些目标的实现将通过每年在M.D.就诊的240名患者来促进。安德森和这些患者返回随访的频率。