Cross-comparison of patient-derived xenografts and derivative organoids and cell lines for translational research in hepatocellular carcinoma

患者来源的异种移植物和衍生类器官和细胞系的交叉比较，用于肝细胞癌的转化研究

基本信息

批准号：
10578710
负责人：
Terence P Gade
金额：
--
依托单位：
PHILADELPHIA VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2023-12-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide with more than 745,000 fatalities in 2012 alone. The majority of patients with HCC present with unresectable disease at diagnosis and a life expectancy of less than 20 months, with only 15% of these patients surviving more than one year after diagnosis. This dismal prognosis underscores the limited therapeutic options for these patients. HCC is a notoriously chemoresistant malignancy and advances in targeted therapeutics have been unsuccessful in improving survival resulting in what some have called “a losing battle” in the development of therapies. This deficiency issues, in large part, from limitations of current preclinical models in (i) recapitulating the inter- and intra-tumoral heterogeneity that characterizes HCC and (ii) predicting patient response to therapeutics. While patient-derived tumor models have been demonstrated to more faithfully recapitulate the heterogeneity of human tumors, there has been limited validation of the translational relevance of these models with respect to their fidelity to the intra- and inter-tumoral mutational heterogeneity that characterizes HCC as well as their ability to provide translationally reliable information for the design, testing and/or outcome evaluation of novel or existing therapies. Indeed, the creation of new patient-derived models of HCC requires rigorous validation of the resulting tumors to confirm their fidelity to the cancer of interest and robust credentialing criteria to ascertain their biological relevance and reliability as surrogates of patient response. In preliminary studies we have: 1) demonstrated the ability to generate PDXs and PDX-derived cell lines from percutaneous biopsies of tumors in patients with intermediate stage HCC and 2) developed methodologies to enable the characterization, validation and optimization of these models. The proposed project will build on this prior work to assess the fidelity and predictive potential of patient-derived models of HCC. We hypothesize that patient-derived models of HCC derived from percutaneous biopsies recapitulate the inter- and intra-tumoral heterogeneity of their parent biopsies and that these models are predictive of patient response to therapy. To test this hypothesis the proposed project will pursue three aims: (1) to define the representation of inter- and intra-tumoral clonal heterogeneity of patient-derived models of HCC through targeted sequencing and digital polymerase chain reaction; (2) to determine the predictive potential of patient-derived models of HCC for response to common HCC therapies; and (3) to investigate the role of HCC tumor initiating cells (TICs) in improving the yield and predictive potential of patient-derived models of HCC. Importantly, the achievement of the proposed aims will transform the utility of patient-derived models of HCC for translational research.

项目概要肝细胞癌（HCC）是全球癌症相关死亡的第二大原因，超过仅 2012 年就有 745,000 人死亡，大多数 HCC 患者的病情无法切除。诊断后预期寿命不足 20 个月，其中只有 15% 的患者存活时间超过 1 个月诊断后一年，这种令人沮丧的预后凸显了这些患者的治疗选择有限。是一种众所周知的化疗耐药性恶性肿瘤，靶向治疗的进展在提高生存率导致了一些人所说的治疗开发中的“一场失败的战斗”。缺陷问题在很大程度上来自于当前临床前模型在（i）概括内部和外部的局限性。肿瘤内异质性是 HCC 的特征，并且 (ii) 预测患者对治疗的反应。虽然患者来源的肿瘤模型已被证明可以更忠实地重现肿瘤的异质性人类肿瘤，这些模型的转化相关性的验证有限他们对 HCC 特征的肿瘤内和肿瘤间突变异质性的忠实度以及他们的能力为新颖或现有的设计、测试和/或结果评估提供翻译可靠的信息事实上，创建新的源自患者的 HCC 模型需要对所得结果进行严格验证。肿瘤以确认其对感兴趣的癌症的忠诚度以及稳健的认证标准以确定其生物学作为患者反应替代指标的相关性和可靠性。在初步研究中，我们：1) 证明了产生 PDX 和 PDX 衍生细胞系的能力对中期 HCC 患者的肿瘤进行经皮活检，2) 开发了方法拟议的项目将在此基础上进行表征、验证和优化。之前的工作评估了源自患者的 HCC 模型的保真度和预测潜力。我们追求从经皮活检衍生的 HCC 患者模型能够重现和其母体活检的肿瘤内异质性，并且这些模型可以预测患者的反应为了检验这一假设，拟议的项目将追求三个目标：（1）定义表征。通过靶向测序分析患者来源的 HCC 模型的肿瘤间和肿瘤内克隆异质性和数字聚合酶链反应；(2) 确定源自患者的 HCC 模型的预测潜力用于对常见 HCC 疗法的反应；以及 (3) 研究 HCC 肿瘤起始细胞 (TIC) 在提高患者来源的 HCC 模型的产量和预测潜力。拟议的目标将改变源自患者的 HCC 模型在转化研究中的效用。