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

描述(由申请人提供)：人们普遍认为，一种疗法适用于所有人的现有临床范例是在有效治疗高度不同的疾病方面缺乏进展的一个主要因素。我们提出了一种新的创新的临床范式，使用患者特定的治疗反应标记物来优化脑癌治疗。我们的长期目标是通过使用强大和超灵敏的加速器质谱仪(AMS)来提高脑瘤(多形性胶质母细胞瘤)患者的存活率。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对化疗的暴露；2)通过开发有效的治疗效果生物标记物来量化个体患者对治疗的肿瘤水平反应；3)通过调整剂量、剂量计划或通过将患者安排在不同的疗程来优化每个患者的治疗。目前，实现这种方法的实验室方法只有部分开发出来。我们的计划是充分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它们的性能。一旦它们的可行性被证明，我们将在未来的脑癌患者的临床研究中使用这些技术。我们在这一第一阶段提案中的具体目标是：1)开发和优化用于量化组织水平[14C]-替莫唑胺(TEMADOR)浓度的高效液相/原子吸收光谱分析方法；2)开发用于量化肿瘤组织中潜在的治疗效果生物标志物的方法；以及3)通过实验建立检测灵敏度，并证明该技术用于支持在患者身上进行的试验的可行性。这些临床试验将首次表征肿瘤替莫唑胺暴露的患者之间的变异性，将这种暴露与疗效的量化标记物联系起来，并表征这些措施与患者结果之间的相关性。最终，我们的目标是开发一种工具，医生可以使用它来安全和快速地建立针对脑癌患者的治疗策略。这项提议为医生使用强大的新技术来改善脑瘤治疗和延长患者生存时间奠定了基础。公共卫生相关性：拟议的努力将验证将当前一种化疗-治疗-适合所有人的范例改变为基于患者对治疗的个人反应的个性化化疗方法的方法。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。

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.