DNAJB1-PRKACA peptide vaccine

Prior molecular studies have focused mainly on the DNAJB1-PRKACA fusion gene, which is pathognomonic for FLC, but no reliable circulating biomarker has been established for FLC diagnosis or disease monitoring...Routine measurement of serum PCT could facilitate earlier recognition of FLC and also provide a non-invasive tool to track treatment response. Future research should validate these findings prospectively, explore the biological mechanisms underlying CALCA overexpression in FLC, and assess whether PCT-guided monitoring can predict prognosis, improve patient outcomes or clinical trial design in this rare malignancy.

A defining molecular hallmark is the DNAJB1-PRKACA fusion gene, found in the majority of cases...Treatment options for advanced disease are limited, with some benefit observed from chemotherapy and targeted agents. Recent developments in molecular therapies and immunotherapy offer promise, but further research and clinical trial participation are essential to improve outcomes in this challenging malignancy.

When compared to wild-type liver progenitor organoids, which exhibit a strong ability to differentiate into hepatocytes, the DNAJB1-PRKACA-expressing liver progenitor organoids displayed a markedly reduced capacity for hepatocyte differentiation. These findings suggest that the DNAJB1-PRKACA fusion gene disrupts the normal differentiation process of liver progenitor cells.

P1, N=56, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Mar 2027 --> Mar 2034 | Trial primary completion date: Mar 2027 --> Mar 2029

We have optimized the HEK-DP-Luc cells for HTS, and here we present our pipeline for primary screening and counter-screening to identify compounds that inhibit DP's downstream transcriptional activity. This HTS platform provides a novel approach for therapeutic drug discovery in FLC.

P1, N=20, Not yet recruiting, University Hospital Tuebingen

We present the case of a 21-year-old male diagnosed with stage IV fibrolamellar hepatocellular carcinoma, studied by the Oncomine Comprehensive Assay genomic sequencing panel with the finding of the DNAJB1-PRKACA fusion and treated with a combination of chemotherapy and immunotherapy based on cisplatin, 5-fluorouracil, adriamycin and nivolumab.

Genetic studies have confirmed that almost all FLC tumors have a fusion protein marker (DNAJB1-PRKACA) encoded by a fusion gene (DNAJB1-PRKACA); It is currently accepted as a diagnostic criterion for FLCs...In this review, we summarize the status of the various FLC models and their features, applications, and limitations. They provide opportunities to understand the cause and characteristics of this deadly disease and are models from which effective treatments can be identified.

Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.

Two doses of the DNAJB1-PRKACA fusion-based neoepitope vaccine Fusion-VAC-XS15 will be applied subcutaneously (s.c.) with a 4-week interval in combination with the anti-programmed cell death-ligand 1 (PD-L1) antibody atezolizumab starting at day 15 after the first vaccination. Clinical trial results will be published in peer-reviewed journals. EU CT Number: 2022-502869-17-01 and ClinicalTrials.gov Registry (NCT05937295).

Nevertheless, we define two functional fusion-specific TCRs, one of which has strong anti-tumor activity in vivo. Together, our results provide insights into the fragmented nature of neoantigen-specific repertoires in humans and indicate routes for clinical development of successful immunotherapies for FLC.

Overall, we propose that LINC00473 could be a viable target for this devastating disease. Schematic was created with BioRender.com.