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首页> 外文学位 >Identification of new strategies for the treatment of glioblastoma multiforme utilizing a pharmacogenomic approach: Genetic profiles associated with patient prognosis and outcome to capecitabine treatment.
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Identification of new strategies for the treatment of glioblastoma multiforme utilizing a pharmacogenomic approach: Genetic profiles associated with patient prognosis and outcome to capecitabine treatment.

机译：使用药物基因组学方法确定新的胶质母细胞瘤治疗新策略：与患者预后和卡培他滨治疗结果相关的遗传特征。

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摘要

Glioblastoma multiforme (GBM) is the most lethal form of primary brain neoplasm with average patient survival between 9 and 15 months even with the most aggressive treatment modalities. Unfortunately, this poor outcome has not appreciably changed in the past 50 years emphasizing the lack of traditional ‘trial and error’ methods in identifying an efficacious treatment for GBM. Pharmacogenomics is greatly impacting cancer research through the development of personalized medicine and rationally designed treatment paradigms for the development of more efficacious and less toxic treatment modalities. The main objective of this research was to utilize a pharmacogenomic approach to identify new strategies for improved GBM therapy. We examined the molecular profiles of tumor tissues obtained from GBM patients with markedly different survival times, as well as non-neoplastic brain tissues, and identified any associations between gene expression with available demographic and clinical data. Furthermore, we investigated associations between gene expression profiles and patient outcome in response to capecitabine and radiotherapy. Results of this clinical study were further explored using in vitro and in vivo glioma models. The significant findings of this dissertation include: (1) identification of the potential GBM tumor-associated prognostic indicators survivin, TS, and USP10, (2) concurrent capecitabine and radiotherapy demonstrated comparable activity to the standard of care for GBM, (3) identification of significant associations between the expression of 24 genes involved in capecitabine metabolism and radiotherapy with patient outcome, (4) development of an 8 gene (RAD54B, FRAP1, DCTD, APEX2, TK1, RRM2, SLC29A1, and ERCC6) expression-based predictor model that accurately identified the clinical outcome of all patients examined, and (5) observation of a similar trend in expression for 21 of the 24 identified genes in capecitabine sensitive and resistant GBM xenograft models. These studies elucidated potential novel mechanisms underlying GBM biology and capecitabine response that may be useful in the design of efficacious GBM tumor-targeted therapies and capecitabine treatment regimens. Importantly, potential biomarkers of GBM patient prognosis and response to capecitabine were identified that may be used in the future stratification of patients towards more efficacious therapy.;Keywords: glioblastoma multiforme, pharmacogenomics, long-term survival, capecitabine, radiotherapy.
机译：多形胶质母细胞瘤（GBM）是最致命的原发性脑肿瘤形式，即使采用最积极的治疗方式，平均患者生存期也为9到15个月。不幸的是，这种糟糕的结果在过去的50年中并没有发生明显的变化，强调了在确定GBM的有效治疗方法方面缺乏传统的“尝试和错误”方法。药物基因组学通过开发个性化医学和合理设计的治疗范例来极大地影响癌症研究，以开发更有效和毒性更小的治疗方式。这项研究的主要目的是利用药物基因组学方法来确定改善GBM治疗的新策略。我们检查了从具有明显不同生存时间的GBM患者获得的肿瘤组织以及非肿瘤性脑组织的分子概况，并鉴定了基因表达与可用人口统计学和临床​​数据之间的任何关联。此外，我们调查了卡培他滨和放疗对基因表达谱与患者预后之间的关系。使用体外和体内神经胶质瘤模型进一步探索了该临床研究的结果。本论文的重要发现包括：（1）确定潜在的GBM肿瘤相关预后指标survivin，TS和USP10，（2）同时卡培他滨和放疗的活性与GBM护理标准相当，（3）鉴定卡培他滨代谢和放疗中涉及的24个基因的表达与患者预后之间的显着关联；（4）开发基于表达的8个基因（RAD54B，FRAP1，DCTD，APEX2，TK1，RRM2，SLC29A1和ERCC6） （5）在卡培他滨敏感性和耐药性GBM异种移植模型中观察到的24种已鉴定基因中有21种的表达趋势相似。这些研究阐明了GBM生物学和卡培他滨反应潜在的潜在新机制，这些机制可能在设计有效的GBM肿瘤靶向疗法和卡培他滨治疗方案时有用。重要的是，已鉴定出GBM患者预后和对卡培他滨的反应的潜在生物标志物，可在未来的患者分层中寻求更有效的治疗方法;关键词：多形胶质母细胞瘤，药物基因组学，长期存活率，卡培他滨，放疗。

著录项

  • 作者

    Grunda, Jessica M.;

  • 作者单位

    The University of Alabama at Birmingham.;

  • 授予单位 The University of Alabama at Birmingham.;
  • 学科 Biology Genetics.;Health Sciences Oncology.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 175 p.
  • 总页数 175
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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