Fibrolamellar Carcinoma: Recent Advances and Unresolved Questions on the Molecular Mechanisms

Lalazar, Gadi; Simon, Sanford M.

doi:10.1055/s-0037-1621710

Cited by 51 publications

(56 citation statements)

References 71 publications

(105 reference statements)

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“…2 Although FLHCC was usually referred as a subtype of HCC, recent researches have demonstrated that FLHCC is actually an independent entity, with distinctive molecular tumor profile, histological features and clinical presentation. 3,4 One of the most feared complications associated with FLHCC is the development of acute onset hyperammonemic encephalopathy (HAE), which was first reported by Sethi et al 5 in 2009, this condition is associated with high mortality. 6 High mortality was related to the ignorance of the physiopa-thology of HAE in patients with FLHCC.…”

Section: Dear Editormentioning

confidence: 99%

Fibrolamellar hepatocellular carcinoma-related hyperammonemic encephalopathy: Up to now and next steps

et al. 2020

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Section: Dear Editormentioning

confidence: 99%

Fibrolamellar hepatocellular carcinoma-related hyperammonemic encephalopathy: Up to now and next steps

et al. 2020

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“…FLHCC is a rare liver cancer that predominantly affects adolescent and young adults with no history of liver disease (Craig et al, 1980; Eggert et al, 2013; Honeyman et al, 2014; Kakar et al, 2005; Lalazar and Simon, 2018; Torbenson, 2012). It does not respond well to chemotherapy and the overall five year survival rate of FLHCC patients is only 30-45% (El-Serag and Davila, 2004; Kakar et al, 2005; Katzenstein et al, 2003; Lim et al, 2014; Mavros et al, 2012; Weeda et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Structures of the PKA RIα holoenzyme with the FLHCC driver J-PKAcα or wild type PKAcα

Cao

Fiesco

et al. 2018

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1Fibrolamellar hepatocellular carcinoma (FLHCC) is driven by J-PKAcα, a kinase fusion chimera 2 2 of the J-domain of DnaJB1 with PKAcα, the catalytic subunit of Protein Kinase A (PKA). Here 2 3 we report the crystal structures of the chimeric fusion RIα 2 :J-PKAcα 2 holoenzyme formed by J-2 4 PKAcα and the PKA regulatory (R) subunit RIα, and the wild type (wt) RIα 2 :PKAcα 2 2 5 holoenzyme. The chimeric and wt RIα holoenzymes have quaternary structures different from 2 6 the previously solved wt RIβ and RIIβ holoenzymes. The chimeric holoenzyme shows an 2 7isoform-specific interface dominated by antiparallel interactions between the N3A-N3A' motifs 2 8of RIα that serves as an anchor for RIα structural rearrangements during cAMP activation. The 2 9wt RIα holoenzyme showed the same configuration as well as a distinct second conformation. In 3 0 the structure of the chimeric fusion RIα 2 :J-PKAcα 2 holoenzyme, the presence of the J-domain 3 1 does not prevent formation of the holoenzymes, and is positioned away from the symmetrical 3 2 interface between the two RIα:J-PKAcα heterodimers in the holoenzyme. The J-domains have 3 3 significantly higher temperature factors than the rest of the holoenzyme, implying a large degree 3 4 of conformational flexibility. Furthermore molecular dynamics simulations were applied to 3 5 analyze the conformational states of chimeric fusion and wt RIα holoenzymes, and showed an 3 6 ensemble of conformations in the majority of which the J-domain was dynamic and rotated away 3 7 from the R:J-PKAcα interface. Thus, rather than affecting the interactions with the regulatory 3 8 subunits, the fusion of the J-domain to the PKAcα alters the conformational landscape of the 3 9 chimeric fusion holoenzymes and potentially, as result, the interactions with other molecules.4 0The structural and dynamic features of these holoenzymes enhance our understanding of the 4 1 fusion chimera protein J-PKAcα that drives FLHCC as well as the isoform specificity of PKA. 4 2 4 3

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“…However, recent advances in the molecular characterization of FLC revealed potential targets including the mTOR pathway or Aurora A kinase. However, even with favorable outcome of mTOR inhibition in single patients [18], no promising results have been published from controlled trials to date [4]. …”

Section: Discussionmentioning

confidence: 99%

“…However, the epidemiology and etiology of FLC differs substantially from typical HCC as the majority of FLC cases are diagnosed in younger patients (< 40 years of age) and are not associated with underlying liver disease. Additionally, recent studies indicate that the biology of FLC differs from typical HCC [1-3] and a DNAJB1-PRKACA fusion transcript has been identified as the signature genetic event in the tumor development of FLC [2, 4]. While several studies indicate that the 5-year survival of patients with FLC (34–70%) is better than for typical HCC (10–16%) [5-7], this difference seems to be mainly attributable to the absence of cirrhosis in most FLC cases [8, 9].…”

Section: Introductionmentioning

confidence: 99%

Progression after Immunotherapy for Fibrolamellar Carcinoma

et al. 2019

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Background: Fibrolamellar carcinoma (FLC) is a rare malignancy of the liver that differs from typical hepatocellular carcinoma (HCC) in several aspects such as the absence of underlying liver disease and occurrence in younger patients. Even though the survival rates in FLC are slightly better than in typical HCC, the prognosis of metastatic FLC remains deleterious. Several reports suggest that systemic chemotherapy regimens can successfully be used to halt disease progression in FLC, while targeted tumor therapy with sorafenib seems to be of limited efficiency. However, results from controlled clinical trials investigating systemic therapies in FLC are virtually nonexistent. Therefore, the choice of treatment often relies on case series with limited numbers of patients. Immunotherapy with checkpoint inhibitors is an emerging cancer therapy in several solid malignancies including HCC. Currently, there do not exist any reports on the use of checkpoint inhibitors in FLC. Case Report: Here, we describe a case of advanced FLC in a young man receiving immunotherapy, who progressed after 3 months of treatment – similar to 2 other patients with advanced FLC at our hospital. Conclusion: While immunotherapy seems to be a promising treatment with limited side effects in several other tumor entities, there is currently no data supporting tumor response in FLC.

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Fibrolamellar Carcinoma: Recent Advances and Unresolved Questions on the Molecular Mechanisms

Cited by 51 publications

References 71 publications

Fibrolamellar hepatocellular carcinoma-related hyperammonemic encephalopathy: Up to now and next steps

Fibrolamellar hepatocellular carcinoma-related hyperammonemic encephalopathy: Up to now and next steps

Structures of the PKA RIα holoenzyme with the FLHCC driver J-PKAcα or wild type PKAcα

Progression after Immunotherapy for Fibrolamellar Carcinoma

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