Cell-Free Nucleic Acids for Early Treatment Response Assessment of Hepatocellular Cancer

Aadel Chaudhuri博士是华盛顿大学放射肿瘤学助理教授。NCI K08 该奖项将提供必要的资金，以实现其职业发展的重要目标，通过允许 他要：1)证明循环中的肿瘤DNA可以作为明确意图后的MRD生物标记物 局部肝癌的治疗，2)循环肿瘤DNA作为肝脏早期反应的生物标志物 癌症免疫检查点阻断，以及3)推断免疫治疗反应的机制 单细胞测序证实了无细胞RNA的去卷积。为了监督乔杜里博士的培训，他 将由丹尼斯·哈拉汉博士指导，他是癌症生物学和放射肿瘤学的知名人物。 马克西米利安·迪恩是无细胞核酸翻译研究的专家，蒂莫西·莱伊博士是一位世界-- 著名的癌症基因组学专家。除了他的导师，乔杜里博士还召集了一组 顾问/合作者，将为他提出的关于无细胞核酸的研究提供专业知识 肝细胞癌的评估。 肝细胞癌是世界范围内癌症死亡的第三大原因，也是立体定向的主要原因。 放射治疗(SBRT)和介入放射学(IR)消融在最终的治疗中起着重要作用。 疾病的早期阶段。这项提案旨在解决接受联合治疗的肝癌患者面临的主要临床挑战 SBRT或IR消融。首先，没有一种标准的监测方式可以可靠地检测分子 治疗结束后的残留病(MRD)。第二，局部治疗后炎症/纤维化 在标准护理监测中，组织变化往往很难与肿瘤复发区分开来 成像。第三，没有可用于评估免疫检查点封锁的标准护理模式 很早。为了应对这些临床挑战，我们计划使用一种方法来分析无细胞DNA，我的方法是 Mentor的实验室开发了一种名为癌症个性化深度测序(CAPP-Seq)的技术， 它依赖于基于捕获的下一代测序，以及一种类似的分析细胞的方法- 游离核糖核酸。CAPP-SEQ可以超灵敏地定量循环中的肿瘤DNA(CtDNA)，并通过跟踪 多重突变和集成数字误差抑制的检测下限为百万分之十。我们 最近发表的CAPP-Seq ctDNA分析可以快速可靠地检测出分子残留病(MRD) 肺癌局部治疗完成后，可早期用于免疫检查点抑制 转移性肺癌的疗效评估(准备中的MS)。我们假设类似的方法 可应用于局限性肝细胞癌，以检测治疗后MRD，并用于反应评估和 免疫检查点阻断治疗晚期肝癌的机制探讨。

Dr. Aadel Chaudhuri is an Assistant Professor of Radiation Oncology at Washington University. The NCI K08 award will provide the funding necessary to achieve important goals for his career development, by allowing him to: 1) Demonstrate that circulating tumor DNA can be used as an MRD biomarker after definitive-intent treatment of localized liver cancer, 2) To use circulating tumor DNA as an early response biomarker for liver cancer immune checkpoint blockade, and 3) To infer mechanisms of immunotherapy response by deconvolution of cell-free RNA confirmed by single cell sequencing. To oversee Dr. Chaudhuri's training, he will be mentored by Dr. Dennis Hallahan, an established figure in cancer biology and radiation oncology, Dr. Maximilian Diehn, an expert in cell-free nucleic acid translational research, and by Dr. Timothy Ley, a world- renowned expert in cancer genomics. In addition to his mentors, Dr. Chaudhuri has assembled a group of advisors/collaborators who will lend expertise to his proposed research on cell-free nucleic acids for response assessment of hepatocellular carcinoma. Hepatocellular carcinoma (HCC) is the number three cause of cancer death worldwide and stereotactic body radiotherapy (SBRT) and interventional radiology (IR) ablation play major roles in the definitive management of early stages of disease. This proposal aims to address major clinical challenges for HCC patients treated with SBRT or IR ablation. First, there is no standard-of-care surveillance modality that can reliably detect molecular residual disease (MRD) after completion of therapy. Second, loco-regional post-treatment inflammatory/fibrotic tissue changes can often be difficult to distinguish from tumor recurrence on standard-of-care surveillance imaging. Thirdly, there is no standard-of-care modality available for assessing immune checkpoint blockade early. To address these clinical challenges, we plan to use a method for profiling cell-free DNA that my mentor's laboratory developed called CAncer Personalized Profiling by deep Sequencing (CAPP-Seq), which relies on capture-based next-generation sequencing, and an analogous method for profiling cell- free RNA. CAPP-Seq allows ultrasensitive quantitation of circulating tumor DNA (ctDNA) and through tracking of multiple mutations and integrated digital error suppression has a detection limit of ~10 parts per million. We recently published that CAPP-Seq ctDNA analysis can reliably detect molecular residual disease (MRD) shortly after localized lung cancer treatment completion, and can be used for immune checkpoint inhibitor early response assessment for metastatic lung cancer (MS in preparation). We hypothesize that similar methods can be applied to localized HCC to detect post-treatment MRD, and for response assessment and mechanism elucidation for advanced HCC patients treated with immune checkpoint blockade.