DNAJB1-PRKACA fusion

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.

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Feb 2027 --> Aug 2029 | Trial primary completion date: Feb 2027 --> Aug 2028

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.

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Phase classification: P1b/2 --> P1/2

P1/2, N=27, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

P1/2, N=27, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Neoplastic FALDs show some unusual molecular profiles compared with non-Fontan ones. The presence of the same alterations in non-lesional cardiac cirrhosis could contribute to the development of FALD.

Preclinical work from our laboratory and others has revealed that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor characterized by glutamine dependence. This study has been registered under NCT06027086 and is expected to begin enrollment in December 2023. Clinical trial information: NCT06027086.

Based on these encouraging results, we established a Phase I open-label, multicentric clinical trial to evaluate the immunogenicity along with safety and toxicity, as well as first signs of efficacy of the FusionVAC-22 based peptide vaccine, combined with the immune checkpoint inhibitor (ICI) atezolizumab, in 20 patients with locally advanced or metastatic FL-HCC or other malignant diseases that carry the DNAJB1-PRKACA fusion transcript. Furthermore, disease control rate, quality of life as well as overall and progression free survival will be assessed. Clinical trial information: NCT05937295.