Translational Medicine and Cancer Therapy with Vasculature-Targeted Agents

项目概述：本K23提案的目的是将研究者多样化的培训经验整合到一个独立的研究项目中，以识别和开发用于癌症治疗个性化管理的遗传和临床生物标志物。为了实现这一目标，梅特兰博士将：1)完成药物计量学、统计遗传学和多变量分析方面的额外教学和辅导教育；2)主要接受Mark Ratain博士（国际公认的早期癌症药物开发和癌症治疗中个体间差异的专家）的指导，设计、执行和解释研究，以确定抑制血管内皮生长因子（VEGF）信号通路（VSP）的生物标志物；3)在芝加哥大学生物科学部肿瘤学和人类遗传学部门的资深同事的指导下进行相关的遗传分析，并设计和执行一项多中心研究，以测试开发的最有希望抑制VSP的生物标志物的实用性。VSP抑制剂构成了一类新的抗癌药物，可以改变脉管系统，从而提高同期化疗的疗效。目前还没有可靠的VSP抑制生物标志物，但可以指导针对特定患者的VSP抑制剂的最佳剂量和选择。为了识别和开发这些生物标志物，研究者将：1 .描述VSP抑制剂索拉非尼与血压之间的关系，并确定血压反应的个体间变异性的药理学基础；2)测试候选基因多态性和临床变量，以了解这种变异性的贡献以及血压变异性与治疗反应的相关性；3)测试典型抗癌干预措施对内皮细胞合成分子血管生成素-2（Ang2）血清浓度的影响，确定影响Ang2血清浓度的内在变量，并确定定量性状位点（与Ang2血清浓度相关的候选基因变异位点）。相关性：新药物和指导其使用的新技术，为医生为特定患者量身定制治疗提供了可能。这种“个性化医疗”有望为癌症患者提供更安全、更有效的治疗。这笔拨款将帮助培训Maitland博士成为进行个性化癌症医学临床和实验室研究的专家。

DESCRIPTION (provided by applicant): Project Summary: The purpose of this K23 proposal is to consolidate the investigator's diverse training experiences into an independent research program that identifies and develops genetic and clinical biomarkers for the individualized management of cancer therapeutics. To accomplish this, Dr. Maitland will: 1) complete additional didactic and tutorial education in pharmacometrics, statistical genetics, and multivariate analysis, 2) be primarily mentored by Dr. Mark Ratain (an internationally recognized expert in both early stage cancer drug development and inter-individual variability in cancer therapeutics) in the design, execution, and interpretation of studies to identify biomarkers for inhibition of the Vascular Endothelial Growth Factor (VEGF) Signaling Pathway (VSP), and 3) be mentored by senior colleagues in the Oncology and Human Genetics Sections of the University of Chicago Biological Sciences Division on relevant genetic analyses, and design and execution of a multi-center study to test the utility of the most promising of the developed biomarkers for inhibition of the VSP. VSP inhibitors constitute a new class of anticancer agents that modify the vasculature and may thereby enhance the efficacy of concurrent chemotherapy. Reliable biomarkers for VSP inhibition do not yet exist but would guide the optimal dosing and selection of VSP inhibitors for a specific patient. To identify and develop such biomarkers the investigator will: 1 Characterize the relationship between the VSP inhibitor sorafenib and blood pressure, and determine the pharmacological basis for interindividual variability in blood pressure response, 2) test candidate gene polymorphisms and clinical variables for contribution to this variability and the relevance of blood pressure variability to treatment response, and 3) test the effects of typical anticancer interventions on serum concentrations of the endothelial cell-synthesized molecule angiopoietin-2(Ang2), determine the intrinsic variables affecting serum concentrations of Ang2, and identify Quantitative Trait Loci (sites for candidate gene variants associated with serum concentrations of Ang2). Relevance: New drugs, and new technologies to guide their use, offer the possibility for physicians to tailor treatment for the specific patient. This "personalized medicine" promises safer, more effective treatment for patients with cancer. This grant will help train Dr. Maitland to be an expert in the conduct of clinical and laboratory studies for personalized cancer medicine.