McDonald Hannah G, Harper Megan M, Hill Kristen, Gao Anqi, Solomon Angelica L, Bailey Charles J, Lin Miranda, Barry-Hundeyin Mautin, Cavnar Michael J, Mardini Samuel H, Pandalai Prakash J, Patel Reema A, Kolesar Jill M, Rueckert Justin A, Hookey Lawrence, Ropeleski Mark, Merchant Shaila J, Kim Joseph, Gao Mei
Division of Surgical Oncology, Department of General Surgery, University of Kentucky, Lexington, KY 40536, USA.
College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Cancers (Basel). 2023 Jun 2;15(11):3036. doi: 10.3390/cancers15113036.
Gastric adenocarcinoma (GAd) is the third leading cause of cancer-related deaths worldwide. Most patients require perioperative chemotherapy, yet methods to accurately predict responses to therapy are lacking. Thus, patients may be unnecessarily exposed to considerable toxicities. Here, we present a novel methodology using patient-derived organoids (PDOs) that rapidly and accurately predicts the chemotherapy efficacy for GAd patients. Endoscopic GAd biopsies were obtained from 19 patients, shipped overnight, and PDOs were developed within 24 h. Drug sensitivity testing was performed on PDO single-cells with current standard-of-care systemic GAd regimens and cell viability was measured. Whole exome sequencing was used to confirm the consistency of tumor-related gene mutations and copy number alterations between primary tumors, PDOs, and PDO single-cells. Overall, 15 of 19 biopsies (79%) were appropriate for PDO creation and single-cell expansion within 24 h of specimen collection and overnight shipment. With our PDO single-cell technique, PDOs (53%) were successfully developed. Subsequently, two PDO lines were subjected to drug sensitivity testing within 12 days from initial biopsy procurement. Drug sensitivity assays revealed unique treatment response profiles for combination drug regimens in both of the two unique PDOs, which corresponded with the clinical response. The successful creation of PDOs within 24 h of endoscopic biopsy and rapid drug testing within 2 weeks demonstrate the feasibility of our novel approach for future applications in clinical decision making. This proof of concept sets the foundation for future clinical trials using PDOs to predict clinical responses to GAd therapies.
胃腺癌（GAd）是全球癌症相关死亡的第三大主要原因。大多数患者需要围手术期化疗，但缺乏准确预测治疗反应的方法。因此，患者可能会不必要地遭受相当大的毒性。在此，我们提出了一种使用患者来源类器官（PDO）的新方法，该方法能快速、准确地预测GAd患者的化疗疗效。从19名患者获取内镜下GAd活检组织，隔夜运送，在24小时内培养出PDO。使用当前GAd标准治疗全身方案对PDO单细胞进行药物敏感性测试，并测量细胞活力。采用全外显子组测序来确认原发性肿瘤、PDO和PDO单细胞之间肿瘤相关基因突变和拷贝数改变的一致性。总体而言，19份活检组织中有15份（79%）适合在标本采集和隔夜运送后24小时内创建PDO并进行单细胞扩增。通过我们的PDO单细胞技术，成功培养出了PDO（53%）。随后，从最初活检取材后的12天内，对两条PDO系进行了药物敏感性测试。药物敏感性分析揭示了两种独特的PDO对联合用药方案具有独特的治疗反应谱，这与临床反应相符。在内镜活检后24小时内成功创建PDO，并在2周内快速进行药物测试，证明了我们的新方法在未来临床决策应用中的可行性。这一概念验证为未来使用PDO预测GAd治疗临床反应的临床试验奠定了基础。
