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
基本信息
- 批准号:7437345
- 负责人:
- 金额:$ 193.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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):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,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史或治疗后的结果的变异性。这些问题反映了对MDS的“生物学”知识的缺乏。最近有新的方法来阐明MDS的分子发病机制。该计划项目拨款(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的主要目标是开发针对低风险和高风险MDS的新疗法。项目1将探讨新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Dr.Molldrem的假设,即如果多肽过表达打破免疫耐受,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。初步数据支持这一假设,并表明接种蛋白酶3衍生表位可以诱导缓解。项目5: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进行治疗。这两个项目都将使用共同的方法来评估生活质量,并且都采用针对可在实验室中量化的目标的治疗方法,从而促进对实验室终点和临床结果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FLT3(项目2)、RAS或PTPN11(Core B)或HOX基因过表达(项目4)的激活突变发生在10-25%的MDS患者中,但随着疾病的发展,同时监测这些突变或试图发现新突变(项目2)的大型基于人群的研究仍然缺乏。例如,项目2、4和核心B之间的相互作用应该允许对Gilliland-Griffin模型中隐含的假设进行评估,即激活赋予生存优势的“1型”突变(例如RAS)。PTPN11, FLT3)通常会伴有阻断分化的“2型”畸变(例如HOX基因过表达),两种1型突变不会发生在同一患者身上。表观遗传现象(如超甲基化)在MDS发病/进展中的作用将在项目3中进行研究;高达30%的MDS患者有高甲基化基因,但这种现象从未在激活突变或HOX过表达的背景下进行过研究。PPG的第三个目标是提高提供准确预后的能力。为此,我们将检验这样一个假设,即基于实验室的项目(项目2- 5)的发现将提供信息,以补充FAB、WHO或IPSS系统提供的信息。例如,初步数据表明,一种名为Ril的基因的高甲基化会导致特别糟糕的预后。M.D. Anderson每年诊治的240名患者以及这些患者返回随访的频率将促进这些目标的实现。
项目成果
期刊论文数量(0)
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HAGOP KANTARJIAN其他文献
HAGOP KANTARJIAN的其他文献
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{{ truncateString('HAGOP KANTARJIAN', 18)}}的其他基金
Epigenetics and Epigenetic Therapy in AML
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- 批准号:
8499744 - 财政年份:2013
- 资助金额:
$ 193.06万 - 项目类别:
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:
7628028 - 财政年份:2005
- 资助金额:
$ 193.06万 - 项目类别:
SPORE University of Texas M.D. Anderson Cancer Center SPORE-Leukemia
SPORE 德克萨斯大学 M.D. 安德森癌症中心 SPORE-白血病
- 批准号:
8472926 - 财政年份:2003
- 资助金额:
$ 193.06万 - 项目类别:
SPORE University of Texas M.D. Anderson Cancer Center SPORE-Leukemia
SPORE 德克萨斯大学 M.D. 安德森癌症中心 SPORE-白血病
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8918439 - 财政年份:2003
- 资助金额:
$ 193.06万 - 项目类别:
SPORE University of Texas M.D. Anderson Cancer Center SPORE-Leukemia
SPORE 德克萨斯大学 M.D. 安德森癌症中心 SPORE-白血病
- 批准号:
9123547 - 财政年份:2003
- 资助金额:
$ 193.06万 - 项目类别:
SPORE University of Texas M.D. Anderson Cancer Center SPORE-Leukemia
SPORE 德克萨斯大学 M.D. 安德森癌症中心 SPORE-白血病
- 批准号:
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- 资助金额:
$ 193.06万 - 项目类别:
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- 批准号:
6786724 - 财政年份:2003
- 资助金额:
$ 193.06万 - 项目类别:
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