Characterization of Predictive Biomarkers for the Clinical Efficacy of PHY906

我们的研究小组将PHY906的临床前活性表征为抗癌药物细胞毒性的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，PHY906生物活性的部分机制涉及调节肿瘤和正常组织的某些关键免疫调节过程和代谢功能，这将反映在接受治疗的患者的血浆免疫因子/生长因子和代谢组谱中。我们希望找出相关的潜在生物标志物，可以用来预测可能从使用PHY906中受益的患者子集。拟议的研究还将开始鉴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将调查血浆中的潜在生物标志物，这些标志物可用于将PHY906的疗效与基于伊立替康的化疗在转移性结直肠癌患者中的临床益处相关联，无论是毒性还是临床活性。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；包括类固醇激素在内的代谢谱；肿瘤DNA水平和突变负荷分布分析，由血浆中肿瘤DNA中K-RAS、B-Raf或PI3K/Akt的突变确定。具体目标2将研究PHY906在免疫调节途径上的作用所涉及的生物活性化合物。这一目标将利用LC/MS光谱分析每个患者样本中PHY906及其代谢物的化学特征，并将每个血浆的活性与几个免疫调节信号通路和体外DNA修复通路相关联，目的是识别血浆中的生物活性化合物。第一个具体目标可能会从系统生物学的角度展示PHY906是如何发挥作用的，这些研究也可能对这些生物标记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PHY906的临床前研究，更重要的是，建立新的方法来确定具有潜在生物学作用的生物活性候选化合物。该项目与本项目中的另外两个项目高度紧密地结合在一起，从这项工作中获得的信息可能会成为将中草药与传统癌症化疗相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.