Characterization of Predictive Biomarkers for the Clinical Efficacy of PHY906

我们的研究小组已经将PHY 906的临床前活性表征为抗癌剂的细胞毒性调节剂以及化疗的细胞保护剂。在这个项目中，我们正在解决一个重要的假设，正如我们的初步临床前结果所表明的那样，PHY 906生物活性的部分机制涉及肿瘤和正常组织的某些关键免疫调节过程和代谢功能的调节，这将反映在治疗患者血浆中的免疫因子/生长因子和代谢组学谱中。我们希望使用多重方法鉴定相关的潜在生物标志物，这些生物标志物可用于预测可能从使用PHY 906中受益的患者子集。拟议的研究也将开始确定这种草药的潜在多个作用部位和生物活性化合物。该项目有两个具体目标：具体目标1将研究血浆中的潜在生物标志物，这些生物标志物可用于在转移性结直肠癌患者中将PHY 906的作用与基于伊立替康的化疗的临床获益（毒性或临床活性）相关联。对于这些研究，将进行一系列广泛的生物标志物分析，其中包括：免疫细胞因子、趋化因子、生长因子的谱;代谢组学谱，包括类固醇激素;肿瘤DNA水平和突变负荷分布分析，通过血浆中肿瘤DNA中K-Ras、B-Raf或PI 3 K/Akt突变的存在来确定。具体目标2将研究参与PHY 906对免疫调节途径的作用的生物活性化合物。该目的将使用LC/MS光谱法表征取自患者的每个样品中PHY 906及其代谢物的化学谱，并将每个血浆的活性与几种免疫调节信号途径和DNA修复途径离体相关，目的是鉴定血浆中的生物活性化合物。第一个具体目标可以从系统生物学的角度显示PHY 906如何工作，这些研究也可能对这些生物标志物与其他癌症治疗的临床结果的相关性产生普遍影响。第二个具体目标将证实我们对PHY 906的临床前研究，更重要的是，建立新的方法来鉴定具有潜在生物活性的候选化合物。本项目与本项目中的其他两个项目高度紧密结合，从本工作中获得的信息可能成为将中草药与常规癌症化疗结合治疗人类癌症的新范式。

Our research group has characterized the preclinical activity of PHY906 as a modulator of cytotoxicity of anticancer agents as well as a cytoprotective agent of chemotherapy. In this project, we are addressing an important hypothesis, as suggested by our preliminary pre-clinical results, that part of the mechanism for the biological activity of PHY906 involves the modulation of certain key immuoregulatory processes and metabolic functions of tumor and normal tissues, which will be reflected in the immunokine/growth factor and metabolomic profiles from plasma of patients under treatment. We hope to identify the relevant potential biomarkers that can be used to predict the subset of patients who may benefit from the use of PHY906 using multiplex approach. The proposed studies will also to begin indentify the potential multiple sites of action and bioactive compounds of this herbal medicine. This Project has two specific aims: Specific Aim 1 will investigate the potential biomarkers in plasma that can be used to correlate the effect of PHY906 with clinical benefit of irinotecan-based chemotherapy, either toxicity or clinical activity, in patients with metastatic colorectal cancer. For these studies, a broad series of biomarker analyses will be conducted, and they include the following: profiles of immunocytokines, chemokines, growth factors; metabolomic profiles including steroid hormones; levels of tumor DNA and mutational load distribution analysis as determined by presence of mutations of K-Ras, B-Raf, or PI3K/Akt from tumor DNA in plasma. Specific Aim 2 will investigate the bioactive compounds involved in the action of PHY906 on immunological regulatory pathways. This aim will characterize the chemical profile of PHY906 and their metabolites in each sample taken from patients using LC/MS spectrometry and correlate each plasma's activity against several immunological regulatory signal pathways and DNA repair pathways ex vivo with the goal of identifying bioactive compounds in plasma. The first specific aim may show how PHY906 works from a systems biology point of view, and these studies may also have a general impact on the correlation of those biomarkers with clinical outcomes for other cancer treatments. The second specific aim will confirm our preclinical studies of PHY906, and more importantly, establish new methodologies to identify bioactive candidate compounds for their potential biological actions. This Project is highly and tightly integrated with the other two proposed Projects in this Program, and the information obtained from this work may serve as a novel paradigm for combining Chinese herbal medicine with conventional cancer chemotherapy to treat human cancers.