Department of Surgery, Mayo Clinic, Rochester, MN, U.S.A.
Department of Medical Oncology, Mayo Clinic, Rochester, MN, U.S.A.
In Vivo. 2023 Sep-Oct;37(5):1940-1950. doi: 10.21873/invivo.13290.
BACKGROUND/AIM: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumor presenting in younger patients without chronic liver disease. Up to 80-100% develop recurrent disease, necessitating additional surgery or systemic treatment. Systemic options and pre-clinical treatment studies are lacking. We previously described patient-derived xenograft (PDX) development, allowing for pre-clinical studies. Herein, we develop FLHCC PDX models and utilize these to define tumor characteristics and determine the efficacy of systemic agents.
Primary and lymph node metastatic tumor tissues were obtained at the time of FLHCC resection in two patients. Tumor lysates were screened for protein upregulation. Cell lines were generated from metastatic and primary tumor tissue. The viability of the cell lines was assessed after treatment with temsirolimus, gemcitabine/oxaliplatin, and FOLFIRINOX. Two PDX models were developed from metastatic tissue. For in vivo studies, tumor-bearing mice were treated with temsirolimus, FOLFIRINOX, and Gemcitabine/oxaliplatin.
PDX models were successfully generated from metastatic FLHCC, which closely recapitulated the original tumor. Upregulation of mTOR was seen in metastatic tissue compared to primary tumors. Cell lines from metastatic tissue demonstrated significant sensitivity to temsirolimus. In vivo testing of PDX models demonstrated a significant response to single-agent temsirolimus with minimal toxicity.
Herein, we demonstrate the feasibility of developing PDX models that closely recapitulate FLHCC. Upregulation of mTOR was seen in metastatic tissue compared to primary tissue. The efficacy of mTOR inhibition with temsirolimus treatment suggests that the upregulation of the mTOR pathway may be a significant mechanism for growth in metastatic lesions and a potential target for therapeutics.
背景/目的：纤维板层肝细胞癌（FLHCC）是一种罕见的肿瘤，发生于无慢性肝病的年轻患者中。多达 80-100%的患者会出现复发疾病，需要进一步手术或系统治疗。目前缺乏系统治疗选择和临床前治疗研究。我们之前描述了患者来源的异种移植物（PDX）的发展，这使其能够进行临床前研究。在此，我们开发了 FLHCC PDX 模型，并利用这些模型来定义肿瘤特征并确定系统药物的疗效。
在两名 FLHCC 患者的肿瘤切除时获得了原发和淋巴结转移肿瘤组织。筛选肿瘤裂解物以确定蛋白质的上调情况。从转移性和原发性肿瘤组织中生成细胞系。在用替西罗莫司、吉西他滨/奥沙利铂和 FOLFIRINOX 处理后评估细胞系的活力。从转移性组织中成功建立了两个 PDX 模型。在体内研究中，用替西罗莫司、FOLFIRINOX 和吉西他滨/奥沙利铂治疗荷瘤小鼠。
成功地从转移性 FLHCC 中生成了 PDX 模型，该模型很好地重现了原始肿瘤。与原发性肿瘤相比，转移性组织中 mTOR 的上调。转移性组织来源的细胞系对替西罗莫司表现出显著的敏感性。PDX 模型的体内测试表明，单药替西罗莫司治疗具有显著的疗效，且毒性最小。
在此，我们证明了开发能够很好地重现 FLHCC 的 PDX 模型的可行性。与原发性组织相比，转移性组织中 mTOR 的上调。替西罗莫司治疗对 mTOR 抑制的疗效表明，mTOR 通路的上调可能是转移病灶生长的重要机制，也是治疗的潜在靶点。
