Table_1_Cell-Free RNA as a Novel Biomarker for Response to Therapy in Head & Neck Cancer.xlsx

Liquid biopsies are gaining more traction as non-invasive tools for the diagnosis and monitoring of cancer. In a new paradigm of cancer treatment, a synergistic botanical drug combination (APG-157) consisting of multiple molecules, is emerging as a new class of cancer therapeutics, targeting multiple pathways and providing a durable clinical response, wide therapeutic window and high level of safety. Monitoring the efficacy of such drugs involves assessing multiple molecules and cellular events simultaneously. We report, for the first time, a methodology that uses circulating plasma cell-free RNA (cfRNA) as a sensitive indicator of patient response upon drug treatment. Plasma was collected from six patients with head and neck cancer (HNC) and four healthy controls receiving three doses of 100 or 200 mg APG-157 or placebo through an oral mucosal route, before treatment and on multiple points post-dosing. Circulating cfRNA was extracted from plasma at 0-, 3- and 24-hours post-treatment, followed by RNA sequencing. We performed comparative analyses of the circulating transcriptome and were able to detect significant perturbation following APG-157 treatment. Transcripts associated with inflammatory response, leukocyte activation and cytokine were upregulated upon treatment with APG-157 in cancer patients, but not in healthy or placebo-treated patients. A platelet-related transcriptional signature could be detected in cancer patients but not in healthy individuals, indicating a platelet-centric pathway involved in the development of HNC. These results from a Phase 1 study are a proof of principle of the utility of cfRNAs as non-invasive circulating biomarkers for monitoring the efficacy of APG-157 in HNC.

液体活检作为一种无创的癌症诊断和监测工具，正日益受到重视。在癌症治疗的新范式下，由多种分子组成的协同植物药组合（APG-157）正崭露头角，成为一类新型的癌症治疗药物，它针对多个途径，提供持久的临床反应、较宽的治疗窗和高度的安全性。监测此类药物的疗效涉及同时对多个分子和细胞事件进行评估。本研究首次提出了一种方法，该方法利用循环血浆中游离RNA（cfRNA）作为药物治疗后患者反应的敏感指标。从六名头颈部癌症（HNC）患者和四名健康对照者中收集血浆，这些受试者通过口服黏膜途径接受100毫克或200毫克的APG-157或安慰剂，在治疗前和多次给药后进行血浆采集。在治疗后0小时、3小时和24小时提取循环cfRNA，随后进行RNA测序。我们进行了循环转录组的比较分析，并能够检测到APG-157治疗后显著的扰动。与炎症反应、白细胞活化和细胞因子相关的转录本在APG-157治疗癌症患者后上调，但在健康个体或安慰剂治疗患者中则没有这种变化。在癌症患者中可以检测到与血小板相关的转录特征，而在健康个体中则没有，这表明血小板为中心的途径可能参与了HNC的发展。这些来自1期研究的成果，证明了cfRNA作为非侵入性循环生物标志物，用于监测APG-157在HNC中疗效的实用性的原理。