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，以实现他的职业发展的重要目标，通过允许 他的目的是：1）证明循环肿瘤DNA可以在明确意图后用作MRD生物标志物 2）使用循环肿瘤DNA作为肝细胞癌的早期反应生物标志物， 癌症免疫检查点阻断，以及3）通过以下方式推断免疫治疗反应的机制： 通过单细胞测序确认无细胞RNA的去卷积。为了监督乔杜里博士的训练， 将由癌症生物学和放射肿瘤学的知名人士丹尼斯·哈拉汉博士指导。 马克西米利安迪恩，无细胞核酸转化研究专家，和博士蒂莫西利，一个世界- 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批 顾问/合作者，他们将为他提出的无细胞核酸研究提供专业知识，以应对 评估肝细胞癌。 肝细胞癌（HCC）是世界范围内第三大癌症死亡原因， 放射治疗（SBRT）和介入放射学（IR）消融在确定性治疗中发挥着重要作用。 疾病的早期阶段。该提案旨在解决HCC患者的主要临床挑战， SBRT或IR消融。首先，没有标准的护理监测模式，可以可靠地检测分子 完成治疗后的残留疾病（MRD）。第二，局部区域治疗后炎症/纤维化 在标准护理监测中，组织变化通常难以与肿瘤复发区分 显像第三，没有可用于评估免疫检查点阻断的标准治疗模式 早了为了应对这些临床挑战，我们计划使用一种方法来分析游离DNA， Mentor的实验室开发了一种名为CAPP-Seq（CAPP-Seq）的深度测序个性化分析， 其依赖于基于捕获的下一代测序，以及用于分析细胞的类似方法， 游离RNA CAPP-Seq允许循环肿瘤DNA（ctDNA）的超灵敏定量， 多突变和集成的数字误差抑制的检测限约为百万分之10。我们 最近发表，CAPP-Seq ctDNA分析可以在短期内可靠地检测分子残留病（MRD 局部肺癌治疗完成后，可早期用于免疫检查点抑制剂 转移性肺癌的缓解评估（MS准备中）。我们假设类似的方法 可应用于局限性HCC，以检测治疗后MRD，并进行缓解评估， 免疫检查点阻断治疗晚期HCC患者的机制阐明。

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.