Predictive Markers to Personalize Medicine for Malignant Glioma

恶性胶质瘤个性化医疗的预测标记

• 批准号: 9128424
• 负责人: KENNETH D ALDAPE
• 金额: $ 23.95万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9128424
• 关键词: Adoption; Amendment; Angiogenesis Inhibitors; Antibodies; Biological Assay; Biological Markers; Blood; Brain; CTLA4 gene; Cancer Center; Classification; Clinical; Clinical Trials; Complex; CpG Island Methylator Phenotype; CpG Islands; Cytotoxic Chemotherapy; Detection; Development; Diagnostic; Diagnostic tests; Dideoxy Chain Termination DNA Sequencing; Discrimination; Disease; Doctor of Medicine; Ensure; Environment; Epigenetic Process; Formalin; Funding; Gene Expression; Gene Expression Profile; Genes; Genetic; Genomics; Glioma; Heterogeneity; Knowledge; Laboratories; MGMT gene; Malignant Glioma; Malignant neoplasm of brain; Messenger RNA; Methodology; Methylation; Molecular; Molecular Analysis; Mutation; New Agents; Outcome; Paraffin Embedding; Pathologic; Patient Selection; Patient-Focused Outcomes; Patients; Phase; Phase II/III Trial; Phenotype; Prognostic Factor; Prognostic Marker; Radiation Therapy Oncology Group; Risk; Stratification Factors; System; Time; Tissue Banks; Tissues; Translating; Tumor Biology; Tumor Tissue; Validation; Work; angiogenesis; antiangiogenesis therapy; base; bevacizumab; biomarker development; biomarker panel; bisulfite; chemoradiation; disease natural history; experience; genetic signature; genome-wide; immunoregulation; improved; improved outcome; innovation; mRNA Expression; molecular diagnostics; molecular marker; molecular subtypes; neuropathology; novel; outcome forecast; patient stratification; patient subsets; personalized medicine; phase III trial; predicting response; predictive marker; prognostic; prognostic signature; promoter; prospective; randomized trial; response; success; targeted agent; targeted treatment; temozolomide; transcriptome sequencing; treatment response; treatment strategy; tumor; tumor heterogeneity

There is a gap in in the availability of predictive biomarkers that are necessary to personalize treatment for patients with GBM. A challenge has been to separate prognostic makers (those that predict the natural history of the disease) from predictive (those that predict response to a particular treatment). l/Vfe hypothesize that effective biomarkers of treatment response must be decoupled from prognostic influences. Furthermore, to maximize clinical utility, these biomarkers must be developed as high-throughput, validated diagnostics applicable to small quantities of formalin-fixed, paraffin-embedded (FFPE) tissue. The specific aims of Project 3 are: 1) Develop a novel clinical diagnostic to classify patients suitable for FFPE tissue and incorporating the most robust molecular prognostic markers. 2) Develop a predictive marker of response to anti-angiogenic therapy. 3) Develop a predictive marker of response to immunomodulation. In the initial MDACC Brain SPORE funding, we developed a 9-gene FFPE biomarker that distinguished favorable from unfavorable patient prognosis. The assay was validated, commercialized, and incorporated as a prospective stratification factor in a phase III trial evaluating the anti-angiogenesis inhibitor bevacizumab [Radiation Therapy Oncology Group (RTOG) 0825]. To further improve survival discrimination, we expanded the 9-gene signature to a more robust 19-gene. In addition, we identified an additional epigenetic prognostic signature, the glioma CpG-island methlylator phenotype (G-CIMP). Using >300 cases from M.D. Anderson Cancer Center (MDACC) we developed a unified four risk group system called the molecular-clinical, prognosticator (MCP) that combines clinicopathologic factors with gene expression, genetic, and epigenetic factors. The analytic approach in constructing the MCP and its improved prognostic classification will allow us to better develop predictive makers independent of prognostic influences. Based on our success in the initial SPORE funding period and leveraging our expertise in biomarker development and our close involvement with the RTOG we know propose renewal of this project.

在预测生物标记物的可用性方面存在缺口，这些标记物是个性化治疗所必需的 肾小球基底膜病患者。一个挑战是将预测标记者(那些预测自然的 疾病病史)来自预测性(预测对特定治疗的反应)。L/Vfe 假设治疗反应的有效生物标志物必须与预后脱钩 影响。此外，为了最大限度地发挥临床效用，这些生物标记物必须开发为高通量、 适用于少量福尔马林固定、石蜡包埋的有效诊断 (FFPE)组织。项目3的具体目标是： 1)开发了一种新的临床诊断方法，以对适合FFPE组织的患者进行分类，并将 最可靠的分子预后标记物。 2)开发抗血管生成治疗反应的预测标记物。 3)开发免疫调节应答的预测标记物。 在最初的MDACC脑孢子基金中，我们开发了一种9基因FFPE生物标记物，它区分了 从不利的患者预后中获得有利的结果。该检测已经过验证、商业化和合并。 在评估抗血管生成抑制剂的III期试验中作为一个前瞻性分层因素 贝伐单抗[放射治疗肿瘤学小组(RTOG)0825]。进一步提高存活率 为了消除歧视，我们将9个基因的签名扩展为更强大的19个基因。此外，我们还确定了一个 其他表观遗传学预后标志，胶质瘤CpG岛甲基化表型(G-CIMP)。vbl.使用 来自M.D.安德森癌症中心(MDACC)的300例病例我们开发了一个统一的四个风险组系统 结合临床病理因素和基因的分子临床预后因子(MCP) 表达、遗传和表观遗传因素。构建MCP的解析法及其应用 改进的预后分类将使我们能够更好地开发独立于 对预后的影响。基于我们在最初孢子资助期取得的成功，并利用我们的 在生物标志物开发方面的专业知识，以及我们与RTOG的密切参与，我们知道RTOG建议更新 这个项目的。