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Precision Medicine Approaches to Integrating Genomics with Cancer Therapy: Applications in Glioblastoma and Lymphoma

机译：将基因组学与癌症治疗相结合的精密医学方法：在胶质母细胞瘤和淋巴瘤中的应用

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摘要

The word "cancer" rarely stands alone, usually prefaced with its anatomical location: lung cancer, prostate cancer, brain cancer. With the advancement of high-throughput omics approaches, specific oncogenic events are reorganizing the landscape of cancer classification, at once creating commonalities between cancers arising in diverse anatomical locations and dividing organ-centric classifications of cancer into a multitude of subtypes. The term "precision medicine" postulates that these new, data-driven groupings based on molecular characterization are the key to making rational therapeutic choices.;The majority of this dissertation addresses the disconnect between extensive molecular characterization and poor cancer therapy outcomes for patients with glioblastoma multiforme (GBM). Despite clear evidence that hyperproduction of the ligand for PDGFR (platelet-derived growth factor receptor alpha) is sufficient to generate GBM of the proneural subtype, anti-PDGFRalpha therapeutics have proven disappointing in clinical trials. Cell adaptation contributes to therapeutic escape. In GBM, proneural tumor cells adopt transcriptional profiles of the mesenchymal subtype. The interconversion between the proneural and mesenchymal transcriptional classes within a tumor population presents both a challenge and an opportunity for therapeutic approaches. The proneural subtype has a proliferation phenotype and presents druggable targets such as PDGFRalpha. The mesenchymal subtype presents an invasive phenotype, but the targets are more challenging to drug. The typical screening for combination therapies that synergize to induce cell death is not as advantageous here, where the disease management is expected to include cytostatic drugs that act on two different aspects of the phenotype: proneurally mediated proliferation and mesenchymally mediated invasion. This work examines the applicability of a combination approach against a proneural target, PDGFRalpha, and mesenchymal targets in the STAT3 (signal transducer and activator of transcription 3) pathway, in the context of a proneural model of GBM.;The work is concluded with collection of work applying precision medicine in other disease contexts, most notably canine lymphoma.
机译：“癌症”一词很少单独出现，通常以其解剖位置开头：肺癌，前列腺癌，脑癌。随着高通量组学方法的发展，特定的致癌事件正在重新组织癌症分类的格局，同时在不同解剖位置产生的癌症之间形成共性，并将以器官为中心的癌症分类分为多种亚型。术语“精密医学”假定基于分子特征的这些新的，数据驱动的分组是做出合理治疗选择的关键。本论文的大部分内容针对胶质母细胞瘤患者广泛的分子特征与不良的癌症治疗结果之间的脱节。多格式（GBM）。尽管有明确的证据表明，PDGFR（血小板源性生长因子受体α）配体的高产足以产生前神经亚型的GBM，但在临床试验中，抗PDGFRalpha疗法令人失望。细胞适应有助于治疗性逃逸。在GBM中，前体肿瘤细胞采用间充质亚型的转录特征。肿瘤群体中前体和间质转录类别之间的相互转化为治疗方法带来了挑战和机遇。神经前体亚型具有增殖表型，并呈现可药物靶向，例如PDGFRalpha。间充质亚型具有侵袭性表型，但靶标对药物更具挑战性。协同诱导细胞死亡的联合疗法的典型筛选在此并不那么有利，因为疾病治疗有望包括作用于该表型的两个不同方面的细胞抑制药物：前体介导的增殖和间质介导的侵袭。这项工作在GBM的神经网络模型的背景下，研究了针对STAT3（信号转导和转录激活因子3）途径中的proneural目标，PDGFRalpha和间充质目标的联合方法的适用性。在其他疾病（尤其是犬淋巴瘤）中应用精密医学的研究。

著录项

  • 作者

    Mooney, Marie R.;

  • 作者单位

    Van Andel Research Institute.;

  • 授予单位 Van Andel Research Institute.;
  • 学科 Genetics.;Oncology.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 153 p.
  • 总页数 153
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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