PO.CL07.01 · 临床研究
利用患者来源类器官和异种移植物评估胃癌的基因组驱动靶向治疗
Genomic-driven targeted therapy evaluation using patient-derived organoids and xenografts in gastric cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：胃癌（GC）表现出显著的分子异质性，妨碍了标准疗法的有效性。迫切需要能够准确反映患者特异性生物学特征的可靠临床前模型，以指导精准治疗。患者来源类器官（PDO）和异种移植物（PDX）为评估靶向治疗提供了互补的平台。
方法：我们建立了代表多种分子亚型的胃癌类器官（GCO），以及配对的PDX和类器官来源异种移植物（ODX）模型。采用组织学、IHC、全外显子组测序和拷贝数分析验证其对患者肿瘤的保真度。基于可干预的基因组改变（TP53突变、PIK3CA突变/扩增、CDK4/6扩增）进行靶向药物筛选。使用PDX模型评估体内治疗疗效和耐药机制，包括通过长期暴露产生的帕博西尼耐药株（3CG-278R）。
结果：GCO保留了其亲本肿瘤和PDX对应模型的形态学、免疫表型和基因组特征，包括PIK3CA、AKT1-3、MTOR、CCND1、CCNE1和CDK4/6的复发性扩增。基因组指导的药物筛选揭示了不同的脆弱性：CDK4/6扩增的GCO对帕博西尼表现出强敏感性（IC₅₀约0.01 μM）；PIK3CA突变的GCO对PI3K抑制剂表现出强效应答（IC₅₀ = 0.004-0.013 μM）；TP53突变的GCO对MDM2抑制剂产生强效应答，并伴有明确的p53/p21通路重新激活。在体内，帕博西尼和AKT抑制剂Ipatasertib显著延缓了肿瘤进展（至终点>40天），并改善了CDK4/6扩增PDX的生存，且毒性极小。帕博西尼耐药PDX模型（3CG-278R）显示CDK6过表达以及以NF-κB和AP-1激活、黏蛋白上调和FOX家族抑癌因子活性降低为标志的转录重编程。帕博西尼联合Ipatasertib的联合治疗恢复了凋亡信号并有效克服了耐药。
结论：这一整合的PDO/PDX/ODX平台准确模拟了胃癌生物学特征，支持基因组指导的治疗分层，并揭示了靶向治疗耐药背后可干预的机制。这些患者来源系统为发现胃癌有效精准治疗和合理药物组合提供了强有力的转化框架。
查看英文原文 English abstract
Background: Gastric cancer (GC) exhibits significant molecular heterogeneity that hampers the effectiveness of standard therapies. Reliable preclinical models that accurately reflect patient-specific biology are urgently needed to inform precision treatments. Patient-derived organoids (PDOs) and xenografts (PDXs) provide complementary platforms for assessing targeted therapies.
Methods: We developed gastric cancer organoids (GCOs) representing diverse molecular subtypes, along with matched PDX and organoid-derived xenograft (ODX) models. Histology, IHC, whole-exome sequencing, and copy-number analysis were used to verify their fidelity to patient tumors. Targeted drug screening was conducted based on actionable genomic alterations (TP53 mutation, PIK3CA mutation/amplification, CDK4/6 amplification). In vivo therapeutic efficacy and resistance mechanisms were evaluated using PDX models, including a Palbociclib-resistant line (3CG-278R) generated through prolonged exposure.
Results: GCOs retained the morphological, immunophenotypic, and genomic features of their parental tumors and PDX counterparts, including recurrent amplifications in PIK3CA, AKT1-3, MTOR, CCND1, CCNE1, and CDK4/6. Genomic-guided drug screening revealed distinct vulnerabilities: CDK4/6-amplified GCOs showed strong sensitivity to Palbociclib (IC₅₀ ~0.01 μM); PIK3CA-mutant GCOs exhibited potent responses to PI3K inhibitors (IC₅₀ = 0.004-0.013 μM); TP53-mutant GCOs responded robustly to MDM2 inhibitors with clear p53/p21 pathway reactivation. In vivo, Palbociclib and the AKT inhibitor Ipatasertib significantly delayed tumor progression (>40 days to endpoint) and improved survival in CDK4/6-amplified PDXs with minimal toxicity. The Palbociclib-resistant PDX model (3CG-278R) showed CDK6 overexpression and transcriptional reprogramming marked by NF-κB and AP-1 activation, mucin upregulation, and decreased FOX-family tumor suppressor activity. Combination therapy with Palbociclib plus Ipatasertib restored apoptotic signaling and effectively overcame resistance.
Conclusions: This integrated PDO/PDX/ODX platform accurately models gastric cancer biology, supports genomic-guided therapeutic stratification, and uncovers actionable mechanisms behind targeted therapy resistance. These patient-derived systems provide a strong translational framework for discovering effective precision treatments and rational drug combinations in gastric cancer.
利益披露 Disclosure
H. Zhang, None..
N. Halmai, None..
J. Diaz Sezati, None..
A. Estrada, None..
L. G. Carvajal-Carmona, None.