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: 7437345
• 负责人: HAGOP KANTARJIAN
• 金额: $ 193.06万
• 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/7437345
• 关键词: New; Approaches; Biology; Treatment; Myelodysplastic

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。尽管如此，还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其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。该计划项目拨款 (PPG) 汇集了具有临床、分子生物学和统计专业知识的研究人员来解决上述问题。 PPG 的主要目标是为低风险和高风险 MDS 开发新疗法。项目1将探讨新靶向疗法在高危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，即如果肽过度表达破坏免疫耐受，则源自正常组织蛋白的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。尽管采用了疫苗接种策略，但项目 5 仍出现高风险 MDS 的患者将在项目 1 中接受治疗。这两个项目将使用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方法，从而激发统计数据评估基于实验室的终点与临床结果之间的关系。 PPG 的第二个目标是进一步了解 MDS 的分子发病机制。尽管 10-25% 的 MDS 患者存在 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规模人群研究（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（例如 RAS.PTPN11、FLT3）时，将定期伴随着阻碍分化的“2型”畸变（例如HOX基因过度表达），同一患者中不会发生两种1型突变。表观遗传现象所发挥的作用，例如项目 3 将检查 MDS 发病机制/进展中的高甲基化；高达 30% 的 MDS 患者具有高甲基化基因，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研究。 PPG 的第三个目标是增强提供准确预测的能力。为此，我们将检验以下假设：基于实验室的项目（项目 2-5）的研究结果将提供补充 FAB、WHO 或 IPSS 系统提供的信息的信息。例如，初步数据表明，Ril 基因的过度甲基化会导致预后特别差。每年在 M.D. Anderson 就诊的 240 名患者以及这些患者返回随访的频率将有助于实现这些目标。