Fibrolamellar carcinoma (FLC) is an uncommon and aggressive form of liver cancer which targets teenagers and young adults. We at Protheragen strive to offer complete diagnostic and therapeutic development services for fibrolamellar carcinoma. These include molecular diagnostics, histopathological evaluations, advanced imaging services, preclinical research, as well as targeted therapies and immunotherapies.
Overview of Fibrolamellar Carcinoma (FLC)
Fibrolamellar carcinoma (FLC) is a scarce and highly aggressive type of liver cancer, which usually appears in the aged 15 and 40. Unlike hepatocellular carcinoma (HCC), FLC does not occur in a chronically diseased liver and is free from cirrhosis and common risk factors like viral hepatitis. The symptoms of the disease are vague and, for the most part, an individual may experience abdominal pain, a mass they can feel in their body, or loss of appetite. It is usually diagnosed in most cases at an advanced stage, which can make therapy very challenging. FLC has a distinctive histological pattern with abundant lamellar bands of fibrosis and has a distinct molecular signature, such as the DNAJB1-PRKACA gene fusion, which is a critical target for diagnostics and therapeutic development.
Fig.1 Molecular mechanisms of fibrolamellar carcinoma. (Dinh T. A.,
et al., 2022)
Pathogenesis of Fibrolamellar Carcinoma (FLC)
The pathogenesis of FLC is primarily accompanied by a specific genetic modification; the fusion gene DNAJB1, PRKACA, which codes for the chimeric protein DNAJ–PKAc. This fusion is the outcome of a somatic heterozygous deletion located on chromosome 19 that replaces the N-terminus portion of the protein kinase A (PKA) catalytic subunit with the heat shock protein 40 (HSP40) co-chaperone's J-domain. This kind of modification of PKA is thought to initiate the oncogenic process through one or more pathways such as MAPK, mTOR, or Wnt/β-catenin. Moreover, FLC tumors are characterized by the overexpression of aromatase, B12 binding protein, and neurotensin, though these markers are not prognostic or therapeutically actionable. The progress made towards understanding FLC has resulted from identifying the fusion DNAJB1-PRKACA, which is now one of the key diagnostic markers.
Diagnostics Development for Fibrolamellar Carcinoma (FLC)
Molecular Diagnostics
The detection of the DNAJB1-PRKACA fusion gene is the cornerstone of FLC diagnosis. This molecular marker is not only pathognomonic for FLC but also critical in differentiating FLC from conventional HCC. RNA sequencing and fluorescence in situ hybridization (FISH) are commonly used techniques for identifying the fusion. These methods provide reliable, accurate detection of the fusion gene, helping to confirm FLC and guide therapeutic decisions.
Histopathological and Immunohistochemical Diagnostics
Histologically, FLC tumors display a unique pattern, characterized by polygonal cells surrounded by fibrous bands. The cells exhibit eosinophilic cytoplasm and are rich in mitochondria, giving them an oncocytic appearance. Immunohistochemical staining for markers such as CK7, CK8, and CD68 helps distinguish FLC from other liver cancers. The dual hepatocytic and biliary phenotype of FLC cells, expressed through these markers, is a key feature used in diagnosing FLC.
Therapeutics Development for Fibrolamellar Carcinoma (FLC)
- Targeted Therapies
Targeted therapies for FLC focus on inhibiting the activity of the DNAJ–PKAc fusion protein or targeting downstream signaling pathways. For example, inhibitors of protein kinase A (PKA) have shown promise in preclinical models. Additionally, agents targeting the MAPK, mTOR, and other kinases are being explored. A recent preclinical study demonstrated that a selective PKAc inhibitor slowed the growth of FLC tumor lines in patient-derived xenograft (PDX) models, highlighting the potential for this therapeutic approach.
- Immunotherapies
Immunotherapies aim to enhance the immune response against FLC. The unique DNAJ–PKAc fusion protein presents an opportunity for targeted immune therapy, as it could serve as a neoantigen. Approaches such as checkpoint inhibitors, adoptive T-cell therapies, and vaccines are being investigated. For instance, a clinical trial at Johns Hopkins University is testing a synthetic peptide vaccine targeting the DNAJ–PKAc fusion protein in combination with immune checkpoint inhibitors, offering a novel strategy for treating FLC.
Table 1. Published data for systemic therapies trialed in FLC. (O'Neill A. F., et al., 2021)
| Authors |
Journal |
Prospective |
Regimen |
# of patients |
Neoadjuvant (n) |
Adjuvant (n) |
Follow-Up |
Comments |
| Standard Chemotherapeutics |
| Bower et al. |
Clinical Oncol 1996 |
N |
Cis/5FU/Epi |
1 |
Y (n = 1) |
Y (n = 1) |
Alive (n = 1), 11 months |
Chemo administered pre- and post-surgery. |
Katzenstein
et al. |
Cancer 2003 |
Y |
Cis/Dox vs. C5V |
10 |
Y (n = 5) |
Y (n = 10) |
Alive (n = 4), median 9 years |
Patients who survived
They were all upfront surgical CRs. One of the 4 is alive with recurrent disease. |
| Targeted Agents |
| Fakih 2014 |
Am J Ther 2014 |
N |
Bevacizumab/Erlotinib |
1 |
Y (n = 1) |
- |
Improved pain |
- |
| Immunotherapeutics |
| Patt et al. |
JCO 2003 |
Y |
5FU + IFN |
8 |
Y (n = 8) |
- |
1CR, 4PR, 1SD, 1PD, 1 minor response |
Responses reported on patients receiving neoadjuvant therapy |
| Al Zahrani et al. |
J or Medical Case Reports 2021 |
N |
atezolizumab/bevacizumab |
2 |
Y (n = 2) |
- |
2PD |
Responses reported on patients receiving neoadjuvant therapy |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers comprehensive services for the development of diagnostics and therapeutics for Fibrolamellar Carcinoma (FLC). Our expertise spans molecular diagnostics, histopathological analysis, and advanced imaging techniques, providing a robust platform for accurate diagnosis. In addition, we specialize in the development of targeted therapies and immunotherapies, leveraging cutting-edge research and preclinical models to advance novel therapeutics for FLC.
Disease Models
- Patient-derived Xenograft hFL-HCC Models
- C57 Mouse Models with DNAJB1-PRKACA Fusion Gene Mutation
- FVB/N Mouse Models
- Homologous Fusion Genes Overexpression DNAJB1a::PRKACAa in Zebrafish
Protheragen's diagnostics and therapeutics development services for FLC are characterized by their multidisciplinary approach, integrating molecular biology, pathology, and preclinical research. Our services are designed to provide comprehensive support at every stage of development, from early discovery to preclinical testing. If you are interested in our services, please feel free to contact us.
References
- Dinh, Timothy A., et al. "A framework for fibrolamellar carcinoma research and clinical trials." Nature reviews Gastroenterology & hepatology 19.5 (2022): 328-342.
- O'Neill, Allison F., et al. "Fibrolamellar carcinoma: An entity all its own." Current Problems in Cancer 45.4 (2021): 100770.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
