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3D-Microtumor_GBM Xenoline Proband Modeling of Kinome-Directed Therapy

3D-微肿瘤_GBM Xenoline 先证带模型的激酶组定向治疗

基本信息

批准号：
8811103
负责人：
Christopher D Willey
金额：
$ 15.99万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811103
关键词：
Address Animals Biological Markers Biological Models Bioreactors Brain Cancer cell line Cell Line Cells Characteristics Clinic Clinical Clinical Research Clinical Trials Design Companions Coupled Data Decision Making Disease Disease model Environment Genetic Genomics Glioblastoma Harvest Health Heterogeneity Human Immunocompromised Host Implant In Vitro Laboratories Life Link Literature Malignant Neoplasms Methods Modeling Molecular Molecular Profiling Mus Neoplasm Transplantation Pathway interactions Patient Selection Patients Peptides Pharmaceutical Preparations Phenotype Phosphotransferases Placenta Pre-Clinical Model Preclinical Drug Evaluation Preclinical Testing Proteins Radiation therapy Research Resected Resistance Selection Criteria Serum Signal Transduction Solutions Specimen Staging System Testing The Cancer Genome Atlas Therapeutic Tissue Embedding Tissues Translating Treatment Efficacy Tumor Tissue Validation Xenograft procedure base clinically relevant drug development drug sensitivity drug testing expectation human disease immortalized cell improved in vivo inhibitor/antagonist kinase inhibitor model development novel novel therapeutics outcome forecast pre-clinical preclinical study proband response screening small molecule success transcriptomics tumor tumor microenvironment tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Current methods of preclinical testing of potential therapeutics have, for the most part, failed to yield a clinical impact. This is particularly true or Glioblastoma multiforme (GBM) where prognosis has increased only by 2-3 months over the last 75 years and is coupled with a 5-year survival of less than 4%. Many promising preclinical studies have failed to live up to expectations when tested clinically. This problem is likely due t: a) limitations of the preclinical model system to predict efficacy and b) lack of reliable biomarkers for proper patient selection. We believe that comprehensively molecularly characterized patient-derived xenograft tumors (xenolines) will provide solutions to both problems. We have characterized a panel of 27 human GBM xenolines at the genomic, transcriptomic, and kinomic (global kinase activity assessment through a peptide substrate microarray) level to generate a "proband" model of clinical disease. We have found these xenolines can recapitulate all four molecular subtypes of GBM identified in The Cancer Genome Atlas while reproducing the key hallmarks of GBM when implanted orthotopically in immunocompromised mice. As a high-throughput extension to our orthotopic pre-clinical model, we have shown that we can grow disaggregated xenoline tumors in a novel three-dimensional (3D) culture system. This system incorporates many cells of the tumor microenvironment to produce "MicroTumors" suitable for higher throughput drug testing. Our comprehensive profiling of these xenolines will allow us to build potential clinical biomarkers of therapeutic response to drugs, particularly for small molecule kinase inhibitors (SMI's). To demonstrate this approach, we have identified novel "kinomic" clusters among these xenolines and have recently presented preliminary evidence that baseline kinomic profiles can differentiate treatment sensitive versus resistant tumors. Therefore, we hypothesize that a two-stage drug testing system utilizing 3D GBM xenoline MicroTumors to screen and profile drug response followed by validation in orthotopic xenoline tumors, will generate a more reliable preclinical therapeutic testing approach translating to more effective drug treatment in patients. A corollary is that xenoline testing will allow for molecular profile integration with drug response information producing a diverse set of probands to which patients with molecularly similar GBM tumors can be assigned for more rational clinical trial design. To demonstrate the feasibility of this system, as proof of concept e will select four drugs and 12 xenolines and: 1) Perform drug screening on MicroTumors grown in a unique 3D environment; 2) Perform secondary drug testing in vivo with selected xenolines based on kinomic profiles and MicroTumor response data; and 3) Integrate chemovulnerability data with molecular profiles to begin to build a drug response prediction system. Relevance: The improved preclinical modeling of GBM not only will provide more clinically reliable drug sensitivity data but also patient selection criteria for smarter clinical trial design.

描述(由申请人提供)：目前潜在疗法的临床前测试方法在很大程度上未能产生临床影响。尤其是多形性胶质母细胞瘤(GBM)，在过去的75年中，预后只增加了2-3个月，而且5年生存率不到4%。许多有希望的临床前研究在临床测试中未能达到预期。这个问题可能是由于：a)临床前模型系统在预测疗效方面的局限性，以及b)缺乏可靠的生物标记物来正确选择患者。我们相信，全面的分子表征患者来源的异种移植瘤(异种)将为这两个问题提供解决方案。我们在基因组水平、转录水平和运动学水平(通过肽底物微阵列评估全球激酶活性)对27个人类GBM异种物质进行了表征，以生成临床疾病的“先证者”模型。我们发现这些异种化合物可以概括癌症基因组图谱中确定的所有四种GBM分子亚型，同时复制GBM的关键特征，当将其原位植入免疫低下的小鼠中时。作为我们临床前原位模型的高通量扩展，我们已经证明了我们可以在新的三维(3D)培养系统中生长分解的异种肿瘤。该系统结合了肿瘤微环境中的许多细胞，以产生适合于更高吞吐量药物测试的“微肿瘤”。我们对这些化合物的全面分析将使我们能够建立潜在的临床生物标记物，用于药物治疗反应，特别是小分子激酶抑制剂(SMI)。为了证明这一方法，我们在这些异种化合物中识别了新的“动态组”，最近提出了初步证据，表明基线动态组可以区分治疗敏感的肿瘤和耐药的肿瘤。因此，我们假设，一个利用3D GBM磷脂微肿瘤筛选和描述药物反应的两阶段药物测试系统，然后在原位磷脂肿瘤中进行验证，将产生更可靠的临床前治疗测试方法，转化为对患者更有效的药物治疗。由此得出的推论是，杂环磷酸盐测试将允许将分子图谱与药物反应信息相结合，产生一组不同的先证者，分子上相似的GBM肿瘤患者可以被分配到这些先证者进行更合理的临床试验设计。为了证明这一系统的可行性，作为概念的证明，e将选择4种药物和12种异烯醇类药物，并：1)对在独特3D环境中生长的微肿瘤进行药物筛选；2)根据动态学数据和微肿瘤反应数据，对选定的异烯烃类化合物进行体内二次药物测试；3)将化学排泄性数据与分子模型相结合，开始建立药物反应预测系统。相关性：改进的GBM临床前建模不仅将提供更可靠的临床药物敏感性数据，还将为更智能的临床试验设计提供患者选择标准。