Medical Scientist Training Program, University of North Carolina, Chapel Hill, NC, USA.
Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA.
Nat Rev Gastroenterol Hepatol. 2022 May;19(5):328-342. doi: 10.1038/s41575-022-00580-3. Epub 2022 Feb 21.
Fibrolamellar carcinoma (FLC), a rare, lethal hepatic cancer, occurs primarily in adolescents and young adults. Unlike hepatocellular carcinoma, FLC has no known association with viral, metabolic or chemical agents that cause cirrhosis. Currently, surgical resection is the only treatment demonstrated to achieve cure, and no standard of care exists for systemic therapy. Progress in FLC research illuminates a transition from an obscure cancer to one for which an interactive community seems poised to uncover fundamental mechanisms and initiate translation towards novel therapies. In this Roadmap, we review advances since the seminal discovery in 2014 that nearly all FLC tumours express a signature oncogene (DNAJB1-PRKACA) encoding a fusion protein (DNAJ-PKAc) in which the J-domain of a heat shock protein 40 (HSP40) co-chaperone replaces an amino-terminal segment of the catalytic subunit of the cyclic AMP-dependent protein kinase (PKA). Important gains include increased understanding of oncogenic pathways driven by DNAJ-PKAc; identification of potential therapeutic targets; development of research models; elucidation of immune mechanisms with potential for the development of immunotherapies; and completion of the first multicentre clinical trials of targeted therapy for FLC. In each of these key areas we propose a Roadmap for future progress.
纤维板层肝细胞癌（FLC）是一种罕见的致命性肝癌，主要发生在青少年和年轻成年人中。与肝细胞癌不同，FLC 与导致肝硬化的病毒、代谢或化学因子没有已知的关联。目前，手术切除是唯一被证明可以治愈的治疗方法，而对于系统治疗，目前还没有标准的治疗方法。FLC 研究的进展揭示了一种从一个模糊的癌症向一个似乎准备揭示基本机制并启动向新疗法转化的癌症的转变。在本路线图中，我们回顾了自 2014 年开创性发现以来的进展，该发现表明几乎所有的 FLC 肿瘤都表达一种特征性的致癌基因（DNAJB1-PRKACA），编码一种融合蛋白（DNAJ-PKAc），其中 HSP40 的热休克蛋白 40（HSP40）共伴侣的 J 结构域取代了 cAMP 依赖性蛋白激酶（PKA）催化亚基的氨基末端片段。重要的进展包括：对由 DNAJ-PKAc 驱动的致癌途径有了更多的了解；确定了潜在的治疗靶点；开发了研究模型；阐明了具有开发免疫疗法潜力的免疫机制；并完成了针对 FLC 的靶向治疗的首次多中心临床试验。在这些关键领域中的每一个领域，我们都提出了未来进展的路线图。
