A framework for fibrolamellar carcinoma research and clinical trials

Abstract

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.

Fig. 1 |. Fibrolamellar carcinoma.

Tumour characteristics (left) and typical clinical features (right). Fibrolamellar carcinoma (FLC) presents, often with vague symptoms, in adolescents and young adults. It is associated neither with liver cirrhosis nor with other factors known to predispose to hepatocellular carcinoma. Primary FLC tumours often grow relatively slowly, but they are highly aggressive and invasive. The cure rate is very low. Common metastatic sites include local lymph nodes, lung and peritoneum. Less frequently observed locations include bone, ovary and intracranial. Diagnosis often occurs only after extensive tumour growth, due to non-specific symptoms and a lack of non-invasive biomarker assays. Image (top left) courtesy of M. Torbenson, Mayo Clinic, USA.

Fig. 2 |. Molecular mechanisms of fibrolamellar carcinoma.

The hallmark genetic lesion of fibrolamellar carcinoma (FLC) is a ~400 kb heterozygous deletion on chromosome 19 that leads to the in-frame fusion of exon 1 of DNAJB1 and exons 2–10 of PRKACA. The translated protein is referred to in this article as the DNAJ–PKAc chimaera. The chimaera recruits heat shock protein 70 (HSP70), conferring additional protein stability. This molecular complex is recruited to A-kinase anchoring protein 13 (AKAP13; also called AKAP-Lbc). A key consequence is activation of multiple downstream signalling cascades including the MAPK pathway and a number of others, as shown. It is not yet known which of these are most critical to oncogenesis or most amenable to therapeutic intervention (see the section ‘Additional therapeutic targets?‘). These biochemical alterations lead to notable changes in the wiring of chromatin (enhancers and super-enhancers), as well as in the activity of transcription factors (for example, cAMP response element binding protein (CREB)) and non-coding RNAs (for example, miR-375 and LINC00473), which together shape the aberrant molecular profiles that promote FLC tumour phenotypes. AURKA, aurora kinase A; EGFR, epidermal growth factor receptor; FGFR1, fibroblast growth factor receptor 1; MAPK, mitogen-activated protein kinase; mTOR, mechanistic target of rapamycin; PKA, cyclic AMP-dependent protein kinase; PKA R₂, PKA regulatory subunit homodimer.