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: 8753978
• 负责人: KENNETH D ALDAPE
• 金额: $ 23.99万
• 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/8753978
• 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; Medicine; Messenger RNA; Methodology; Methylation; Molecular; Molecular Analysis; Mutation; New Agents; Outcome; Paraffin Embedding; Pathologic; Patient Selection; Patients; Phase; Phase II/III Trial; Phase III Clinical Trials; 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; bisulfite; chemoradiation; disease natural history; experience; genome-wide; immunoregulation; improved; innovation; mRNA Expression; molecular marker; neuropathology; novel; outcome forecast; prognostic; promoter; prospective; randomized trial; response; response marker; success; temozolomide; treatment response; treatment strategy; tumor

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.

预测生物标志物的可用性存在差距，这是个性化治疗的必要条件 GBM患者。一个挑战是分开预后制造商（那些预测自然的人 该疾病的历史）（预测对特定治疗的反应的疾病）。 l/vfe 假设必须将有效的治疗反应生物标志物与预后脱钩 影响。此外，为了最大程度地提高临床实用性，必须开发这些生物标志物作为高通量， 经过验证的诊断，适用于少量的福尔马林固定，石蜡包裹的诊断 （FFPE）组织。项目3的具体目的是： 1）开发一种新型的临床诊断，以对适合FFPE组织的患者进行分类并结合 最健壮的分子预后标记。 2）发展对抗血管生成疗法的反应的预测标记。 3）发展对免疫调节反应的预测标记。 在最初的MDACC脑孢子资金中，我们开发了一个9基因FFPE生物标志物 不利的患者预后有利。该测定法经过验证，商业化和成立 作为评估抗血管生成抑制剂的III期试验中的前瞻性分层因子 贝伐单抗[放射治疗肿瘤学组（RTOG）0825]。进一步提高生存 歧视，我们将9基因签名扩展到了更强大的19基因。此外，我们确定了 其他表观遗传预后签名，神经胶质瘤CpG-Island甲基散肌表型（G-CIMP）。使用 > M.D. Anderson癌症中心（MDACC）的300例案例我们开发了一个统一的四风险组系统 称为分子临床预后剂（MCP），将临床病理因子与基因结合 表达，遗传和表观遗传因素。构建MCP及其ITS的分析方法 改进的预后分类将使我们能够更好地开发独立于 预后影响。根据我们在初始孢子资金期间的成功，并利用我们的 生物标志物开发方面的专业知识以及我们与我们知道续约的RTOG的密切参与 这个项目。