Patient-specific therapy of glioblastoma using lightly-labeled [14C]-temozolomide

使用轻标记的 [14C]-替莫唑胺对胶质母细胞瘤进行患者特异性治疗

• 批准号: 7484059
• 负责人: Ali Arjomand
• 金额: $ 10.29万
• 依托单位: ACCIUM BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-04 至 2009-02-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7484059
• 关键词: Affect; Animal Model; Biological Assay; Biological Markers; Brain Neoplasms; Cancer Patient; Cell Culture System; Cells; Clinical; Clinical Research; Clinical Trials; Cultured Cells; DNA; DNA Repair; Detection; Development; Diagnostic tests; Disease; Dose; Exposure to; Future; Glioblastoma; Glioma; Goals; Heterogeneity; High Pressure Liquid Chromatography; Human; Individual; Label; Laboratories; Laboratory Research; MGMT gene; Malignant neoplasm of brain; Measures; Methodology; Methods; Modeling; Numbers; Outcome; Parents; Patients; Performance; Phase; Physicians; Positioning Attribute; Procedures; Public Health; Rattus; Research; Research Design; Schedule; Services; Staging; Techniques; Technology; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Tumor Tissue; accelerator mass spectrometry; adduct; analytical method; base; cancer therapy; cancer type; chemotherapy; commercialization; improved; innovation; method development; new technology; repair enzyme; research study; response; temozolomide; tool; tumor

DESCRIPTION (provided by applicant): It is widely accepted that the existing clinical paradigm of one treatment fits all is a major factor in the lack of progress in the effective treatment of a highly heterogeneous diseases. We propose a new innovative clinical paradigm that optimizes brain cancer therapy using patient-specific markers of therapeutic response. Our long-term objective is to improve survival in brain tumor (glioblastoma multiforme) patients by utilizing a powerful and ultra-sensitive technology, Accelerator Mass Spectrometry (AMS). Our approach follows these three steps: 1) Quantify tumor exposure to chemotherapy in individual patients at the earliest stages of therapy; 2) Quantify tumor-level response to treatment in individual patients by developing validated biomarkers of therapeutic efficacy; 3) Optimize each patient's treatment by adjusting dose, dose schedule, or by placing the patient on a different course of therapy. Currently, laboratory methods enabling this approach are only partially developed. Our plan is to fully develop and validate innovative laboratory techniques and demonstrate their performance in cell and animal models. Once their feasibility has been demonstrated, we will employ these techniques in future clinical studies of brain cancer patients. Our specific aims in this Phase I proposal are to: 1) develop and optimize HPLC/AMS analytical methods for quantifying tissue-level [14C]- temozolomide (temador) concentration; 2) develop methodologies for quantifying potential biomarkers of therapeutic efficacy in tumor tissue; and 3) establish assay sensitivity experimentally and demonstrate the feasibility of this technique in support of trials conducted in patients. These clinical trials will characterize, for the first time, the inter-patient variability in tumor temozolomide exposure, relate that exposure to quantitative markers of therapeutic efficacy, and characterize the correlation between these measures and patient outcome. Ultimately, our goal is develop a tool physicians can use to safely and quickly establish patient- specific strategies for treatment of brain cancer patients. This proposal lays the groundwork for physicians to employ powerful new technologies to improve brain tumor treatment and prolong patient survival. PUBLIC HEALTH RELEVANCE: The proposed effort will validate approaches that change the current paradigm of one-chemotherapy-treatment-fits-all to a personalized chemotherapy approach that is based on the patient's individual response to the treatment. This approach may be adapted to other types of cancers, and with further development, may have far reaching benefits that affect an even greater number of patients.

描述（由申请人提供）：人们普遍认为，现有的一种治疗方法适用于所有疾病的临床范例是高度异质性疾病有效治疗缺乏进展的主要因素。我们提出了一种新的创新临床模式，使用患者特异性治疗反应标志物优化脑癌治疗。我们的长期目标是通过利用强大的超灵敏技术加速器质谱（AMS）来提高脑肿瘤（多形性胶质母细胞瘤）患者的生存率。我们的方法遵循以下三个步骤：1）在治疗的最早阶段量化个体患者中肿瘤暴露于化疗; 2）通过开发有效的治疗疗效生物标志物来量化个体患者中肿瘤水平对治疗的反应; 3）通过调整剂量，剂量方案或将患者置于不同的治疗过程中来优化每个患者的治疗。目前，实验室方法，使这一方法只是部分开发。我们的计划是全面开发和验证创新的实验室技术，并在细胞和动物模型中展示其性能。一旦其可行性得到证实，我们将在未来的脑癌患者的临床研究中采用这些技术。我们在I期提案中的具体目标是：1）开发和优化用于定量组织水平[14 C]-替莫唑胺（替莫唑胺）浓度的HPLC/AMS分析方法; 2）开发用于定量肿瘤组织中治疗有效性的潜在生物标志物的方法; 3）通过实验建立测定灵敏度，并证明该技术在支持患者试验中的可行性。这些临床试验将首次表征肿瘤替莫唑胺暴露的患者间变异性，将该暴露与治疗疗效的定量标志物相关联，并表征这些措施与患者结局之间的相关性。最终，我们的目标是开发一种工具，医生可以用来安全，快速地建立患者特定的策略，治疗脑癌患者。该提案为医生采用强大的新技术来改善脑肿瘤治疗和延长患者生存期奠定了基础。公共卫生相关性：拟议的努力将验证的方法，改变目前的模式，一个化疗治疗适合所有的个性化化疗方法，是基于患者的个人反应的治疗。这种方法可能适用于其他类型的癌症，随着进一步的发展，可能会产生深远的好处，影响更多的患者。