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.

项目摘要肝细胞癌（HCC）是全球与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患者出现无法切除的疾病诊断和预期寿命少于20个月，其中只有15％的患者存活多个诊断后的一年。这种令人沮丧的预后强调了这些患者的治疗选择有限。 HCC 众所周知的化学抗性恶性肿瘤和靶向疗法的进步未成功改善生存，导致一些人在疗法发展中所谓的“失败战”。这不足问题在很大程度上是从（i）概括了当前临床前模型的局限性的特征HCC和（ii）预测患者对治疗的反应的肿瘤内异质性。尽管已经证明了患者来源的肿瘤模型，以更忠实地概括人类肿瘤，对这些模型相关的翻译相关性的验证有限它们对特征HCC及其能力的富有内部和umenialiention突变异质性的忠诚度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疗法。实际上，创建新的患者衍生的HCC模型需要严格验证由此产生的肿瘤以确认其对感兴趣癌症的保真度和强大的凭证标准以确定其生物学相关性和可靠性与患者反应的替代物。在初步研究中，我们有：1）证明了从中级HCC患者肿瘤的经皮活检和2）开发了启用这些模型的表征，验证和优化。拟议的项目将建立在此基础上先前的工作，以评估HCC患者衍生模型的保真度和预测潜力。我们假设源自经皮活检的HCC的患者衍生模型概括了和父母活检的肿瘤内异质性，这些模型可以预测患者的反应接受治疗。为了检验这一假设，拟议的项目将追求三个目标：（1）定义表示形式通过靶向测序的患者衍生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HCC患者衍生模型的预测潜力以应对常见的HCC疗法；（3）研究HCC肿瘤启动细胞（TICS）在提高HCC患者衍生模型的产量和预测潜力。重要的是，成就拟议的目标将改变HCC患者衍生模型的效用进行转化研究。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Association Between Proton Pump Inhibitor Exposure and Key Liver-Related Outcomes in Patients With Cirrhosis: A Veterans Affairs Cohort Study.

DOI：
10.1053/j.gastro.2022.03.052
发表时间：
2022-07
期刊：
Gastroenterology
影响因子：
29.4
作者：
通讯作者：

External Validation of the FIPS Score for Post-TIPS Mortality in a National Veterans Affairs Cohort.

DOI：
10.1007/s10620-021-07307-5
发表时间：
2022-09
期刊：
DIGESTIVE DISEASES AND SCIENCES
影响因子：
3.1
作者：
Chapin, Sara E.;Goldberg, David S.;Kaplan, David E.;Mahmud, Nadim
通讯作者：
Mahmud, Nadim

Performance of risk prediction models for post-operative mortality in patients undergoing liver resection.

DOI：
10.1016/j.amjsurg.2022.07.028
发表时间：
2022-08
期刊：
American journal of surgery
影响因子：
3
作者：
N. Mahmud;Sarjukumar Panchal;F. Turrentine;D. Kaplan;V. Zaydfudim
通讯作者：
N. Mahmud;Sarjukumar Panchal;F. Turrentine;D. Kaplan;V. Zaydfudim

Algorithms to Identify Alcoholic Hepatitis Hospitalizations in Patients with Cirrhosis.

DOI：
10.1007/s10620-021-07321-7
发表时间：
2022-09
期刊：
DIGESTIVE DISEASES AND SCIENCES
影响因子：
3.1
作者：
Panchal, Sarjukumar A.;Kaplan, David E.;Goldberg, David S.;Mahmud, Nadim
通讯作者：
Mahmud, Nadim

Variability in biopsy quality informs translational research applications in hepatocellular carcinoma.

DOI：
10.1038/s41598-021-02093-6
发表时间：
2021-11-23
期刊：
Scientific reports
影响因子：
4.6
作者：
Weinfurtner K;Cho J;Ackerman D;Chen JX;Woodard A;Li W;Ostrowski D;Soulen MC;Dagli M;Shamimi-Noori S;Mondschein J;Sudheendra D;Stavropoulos SW;Reddy S;Redmond J;Khaddash T;Jhala D;Siegelman ES;Furth EE;Hunt SJ;Nadolski GJ;Kaplan DE;Gade TPF
通讯作者：
Gade TPF