DNAJB1-PRKACA peptide vaccine / BMS, Sidney Kimmel Comprehensive Cancer Center - LARVOL DELTA

Molecular profile of hepatocellular carcinoma (HCC) in older (OA) versus younger adults (YA) receiving tyrosine kinase inhibitors: Does age matter? (ASCO 2025) - "OA was not associated with MKI-TOT such as sorafenib or cabozantinib. However, OA was associated with a shorter TOT (HR 1.6, p < 0.01) on lenvatinib (len)...Multivariate analysis revealed that OA was independently associated with shorter len-TOT (HR 1.6, p 0.01), while CTNNB1 mutations and DNAJB1-PRKACA fusions were independently associated with longer len-TOT (HR 0.4-0.5, both p < 0.05)... OA was associated with differing survival trends between whites and Asian/PI compared to Black/AA. Further, OA was associated with shorter len-TOT, potentially due to anti-angiogenic toxicity. Our limitations include an inability to investigate race-based differences on len-TOT due to small sample sizes (Black/AA: n = 18, Asian/PI: n = 15) and the lack of toxicity and geriatric assessment data."

Clinical • IO biomarker • Hepatocellular Cancer • Oncology • Solid Tumor • CDKN2A • CTNNB1 • DNAJB1 • PD-L1 • PRKACA • TP53

A therapeutic vaccine for fibrolamellar hepatocellular carcinoma. (ASCO 2025) - P1 | "The primary objectives were safety and T cell responses, defined as 2.5-fold increase of interferon gamma (IFN-γ)-producing DNAJB1-PRKACA chimera-specific T cells in the peripheral blood after week 10 (priming phase)...FLC-Vac, consisting of a peptide encoding the DNAJB1-PRACA fusion plus poly-ICLC adjuvant, was administered on weeks 0, 1, 2, 3, 6, 9 during the priming phase of the study. Nivolumab, 3 mg/kg, followed by ipilimumab, 1 mg/kg, was administered every 3 weeks for 4 doses during the priming phase... Our findings demonstrate the potential for therapeutic vaccines targeting DNAJ-PKAc in FLC and suggest a rubric for evaluating effective anti-neoantigen immunity."

Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • IFNG • PRKACA

Napabucasin analogues with increased bioavailability and efficacy in fibrolamellar hepatocellular carcinoma (AACR 2025) - "In FLC, a deletion of 400,000 base pairs occurs in a chromosome 19 copy, leading to the formation of a fusion protein comprising heat shock protein DNAJB1 and the catalytic subunit of Protein Kinase A (DNAJB1-PRKACA). Napabucasin is known to work in multiple signaling pathways and have been shown cytotoxic against both PDX and direct-from-patient FLC tumor cells. We anticipate that the organic synthesis and development of optimized Napabucasin analogues, along with the evaluation of their cytotoxicity and proliferation effectiveness compared to the parent compound, Napabucasin, will result in compounds with improved bioavailability and efficacy, particularly in FLC model cell lines (FLX1 and Huh7-Chimera)."

Clinical • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

Spatially resolved gene expression analysis of primary and metastatic fibrolamellar hepatocellular carcinoma (FLC) (AACR 2025) - "Furthermore, we succeeded in labeling the neoplastic cells using a custom-designed probe against the DNAJB1-PRKACA chimeric transcript which we included in the standard probe library...Here we present a spatially and temporally resolved transcriptome atlas of FLC. This rich and valuable resource will be critical for understanding FLC biology and ultimately developing novel therapeutics."

IO biomarker • Metastases • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

Treatment of fibrolamellar carcinoma with hepatocellular carcinoma -specific amplitude-modulated radiofrequency electromagnetic fields (AACR 2025) - "Proliferation and stemness of the HepG2 and H33 [HepG2 (DNAJB1-PRKACA)] cell lines were inhibited following HCCMF treatment. Results show the presence of the FLC fusion protein (DNAJB1-PRKACA) does not inhibit the potential of HCCMF as a novel systemic targeted therapy for FLC. This proof-of-principle data shows significant potential for the treatment of FLC."

Hepatocellular Cancer • Oncology • Solid Tumor • CACNA1H • CAV3 • DNAJB1 • PRKACA

Combination immunotherapy promotes integrated anti-tumor immunity in fibrolamellar carcinoma (AACR 2025) - "Characterized molecularly by a conserved DNAJB1-PRKACA fusion oncogene and histologically by dense intratumoral stromal bands, the unique FLC tumor immune microenvironment (TIME) results in limited intrinsic anti-tumor immunity and poor clinical responses to single-agent immune checkpoint blockade...Targeting these pathways with combination CXCR4 inhibition (AMD3100) and PD-1 blockade in a human tumor slice culture model system significantly increased tumor cell death relative to isotype control and both monotherapies...Together, our findings demonstrate that combination CXCR4 and PD-1 inhibition cooperatively overcome both immune exclusion and immunosuppression in the FLC TIME. Furthermore, these results provide pre-clinical evidence for rational selection of combination immunotherapy in a rare tumor type that currently has no effective systemic therapies."

IO biomarker • Late-breaking abstract • Hepatocellular Cancer • Oncology • CXCL12 • CXCR4 • DNAJB1 • PRKACA

A novel high-throughput screening platform to identify inhibitors of DNAJB1-PRKACA-driven transcriptional activity in fibrolamellar carcinoma. (PubMed, SLAS Discov) - "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."

Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • LINC00473 • PRKACA

Fibrolamellar hepatocellular carcinoma treated with chemotherapy and immunotherapy: a rare entity with unique characteristics. (PubMed, Rev Esp Enferm Dig) - "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."

Journal • Hepatocellular Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

FusionVAC22_02: Peptide Vaccine for Fibrolamellar Hepatocellular Carcinoma Patients and Other Tumor Entities Carrying the Driver Fusion DNAJB1-PRKACA (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: University Hospital Tuebingen

New P1 trial • Hepatocellular Cancer • Oncology • Solid Tumor • IFNG

Rate of gene fusion/rearrangement identification in GI cancers as sequencing evolved from limited panels to whole exome sequencing. (ASCO-GI 2025) - "Rearrangements included NTRK1/2/3, FGFR2/3, NRG, ALK, ROS, CLDN18-ARHGAP, RSPO2/3, DNAJB1-PRKACA, BRAF, MET and RET... The use of more comprehensive NGS panels such as WES did not appear to increase the detection rate for fusion/rearrangements. In resource limited settings, limited panels may suffice. The number of GI cancer patients getting NGS testing has increased over time."

Whole exome sequencing • Gastrointestinal Cancer • Oncology • ALK • ARHGAP • BRAF • CLDN18 • DNAJB1 • FGFR2 • NRG1 • NTRK • NTRK1 • NTRK2 • NTRK3 • PRKACA • RET • RSPO2

T cell receptor sequence clustering correlates with response to combination immunotherapy in fibrolamellar carcinoma (SITC 2024) - P1 | "Methods 12 patients were treated with a 24mer DNAJB1-PRKACA synthetic long peptide vaccine with poly-ICLC in combination with ipilimumab and nivolumab. Ethics Approval This study was approved by the Johns Hopkins University School of Medicine Institutional Review Board (IRB), IRB approval number 00222681; and the St. Jude Children's Research Hospital Institutional Review Board, IRB approval number 21-0790."

IO biomarker • Late-breaking abstract • Hepatocellular Cancer • Oncology • DNAJB1 • PRKACA

Models of fibrolamellar carcinomas, tools for evaluation of a new era of treatments. (PubMed, Front Immunol) - "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."

Journal • Review • Hepatocellular Cancer • Oncology • DNAJB1 • PRKACA

FusionVAC22_01: Phase I study to evaluate treatment with a DNAJB1-PRKACA fusion transcript peptide vaccine and immune checkpoint inhibition in patients with fibrolamellar hepatocellular carcinoma and other tumor entities that harbor the oncogenic driver fusion – Trial in Progress (DGHO 2024) - P1 | "Based on these promising data, we started a Phase I open label, multicentric clinical trial evaluating immunogenicity along with safety, toxicity and first signs of efficacy of Fusion-VAC-XS15 (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 cancer with proven DNAJB1-PRKACA fusion transcript without available standard therapy (Hackenbruch et al. Also, disease control rate, quality of life, and overall-/ progression-free survival will be evaluated. So far, 4 patients have been vaccinated."

Checkpoint inhibition • Clinical • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Immunology • Oncology • Pancreatic Cancer • Solid Tumor • DNAJB1 • PRKACA

DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming. (PubMed, Cancer Discov) - "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."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • GNAS • PRKACA • STK11

Exploiting a critical vulnerability to glutamine antimetabolite therapy in fibrolamellar hepatocellular carcinoma (FLC) (CRI-ENCI-AACR ICIC 2024) - P1/2 | "Our preliminary data using preclinical models of FLC and human biospecimens from FLC patients shows that the DNAJB1-PRKACA fusion results in a metabolic rewiring of the tumor cell characterized by glutamine dependence...Furthermore, the combination of JHU-083, a glutamine antagonist, in combination with checkpoint inhibitor therapy dramatically improved antitumor effects and enhanced survival in a preclinical model of FLC...Patients will receive DRP-104 (145 mg s.c. twice weekly) in combination with a fixed dose of durvalumab (1500 mg i.v. every 28 days)...Secondary objectives include progression free survival (PFS), overall survival (OS), and immunological correlates (NCT06027086). Through this trial, we will test the hypothesis that glutamine antagonism in FLC reverses resistance to immune checkpoint inhibitor (ICI) therapy through modulating the TiME."

CNS Disorders • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Metabolic Disorders • Oncology • Psychiatry • Solid Tumor • DNAJB1 • PRKACA

HYPERAMMONIEMIC ENCEPHALOPATHY AND SECONDARY OTC DEFICIENCY IN FIBROLAMELLAR HEPATOCELLULAR CARCINOMA (SSIEM 2024) - "Molecular investigation of OTC was negative, while NGS identified in tumor tissue the somatic DNAJB1-PRKACA fusion gene... HAE in cancer patients is usually triggered by tumour necrosis/growth or by chemotherapy. Differently, in FHCC this severe and relatively frequent complication is caused by a complex epigenetic cascade of events. Our report highlights the need of increasing the awareness in the metabolic community on the occurrence of HAE in FHCC and on its peculiar pathophysiological mechanism."

CNS Disorders • Gastrointestinal Cancer • Genetic Disorders • Hepatocellular Cancer • Oncology • Solid Tumor • AURKA • DNAJB1 • MYC • PRKACA

FusionVAC22_01: A phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion. (ASCO 2024) - P1 | " Building on these promising outcomes, we have initiated a Phase I open-label, multicentric clinical trial to assess the immunogenicity, safety, toxicity, and initial signs of efficacy of the FusionVAC-22-based peptide vaccine combined with the immune checkpoint inhibitor (ICI) atezolizumab. Bauer et al., Nat. Commun, 2022."

Checkpoint inhibition • Clinical • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Immunology • Oncology • Pancreatic Cancer • Solid Tumor • DNAJB1 • PRKACA

FusionVAC22_01: a phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion. (PubMed, Front Oncol) - P1 | "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)."

Checkpoint inhibition • Journal • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • PRKACA

DNAJB1-PRKACA fusion neoantigens elicit rare endogenous T cell responses that potentiate cell therapy for fibrolamellar carcinoma. (PubMed, Cell Rep Med) - "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."

IO biomarker • Journal • Tumor-specific neoantigens • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • CD8 • DNAJB1 • PRKACA

DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma. (PubMed, PLoS Genet) - "Overall, we propose that LINC00473 could be a viable target for this devastating disease. Schematic was created with BioRender.com."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • DNAJB1 • LINC00473 • PRKACA

FusionVAC22_01: A phase I clinical trial evaluating a DNAJB1-PRKACA fusion transcript-based peptide vaccine combined with immune checkpoint inhibition for fibrolamellar hepatocellular carcinoma and other tumor entities carrying the oncogenic driver fusion. (ASCO-GI 2024) - P1 | " 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."

Checkpoint inhibition • Clinical • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Pancreatic Cancer • Solid Tumor • DNAJB1 • PRKACA

Glutamine antagonist DRP-104 in combination with durvalumab in patients with advanced fibrolamellar carcinoma (FLC) following progression on prior anti-PD(L)1 therapy. (ASCO-GI 2024) - P1b/2 | "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."

Clinical • Combination therapy • Metastases • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • DNAJB1 • PRKACA

Histopathological Spectrum and Molecular Characterization of Liver Tumors in the Setting of Fontan-Associated Liver Disease. (PubMed, Cancers (Basel)) - "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."

Journal • Tumor mutational burden • Biliary Cancer • Cholangiocarcinoma • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Liver Cancer • Oncology • Solid Tumor • CTNNB1 • DNAJB1 • FGFR3 • GNAS • NRAS • PRKACA • TMB

GalNAc-conjugated siRNA targeting the DNAJB1-PRKACA fusion junction in Fibrolamellar Hepatocellular Carcinoma. (PubMed, Mol Ther) - "Knockdown of DNAJB1::PRKACA results in durable growth inhibition of FLC PDX in vivo with no detectable toxicities. Our results suggest that this approach could be a treatment option for FLC patients."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor • ASGR • DNAJB1 • PRKACA

A DNAJB1-PRKACA fusion peptide vaccine combined with ipilimumab and nivolumab elicits polyclonal fusion-specific T cell responses in fibrolamellar carcinoma (SITC 2023) - P1 | "Results A young male with histologically confirmed FLC was treated with a 24mer DNAJB1-PRKACA synthetic long peptide vaccine with poly-ICLC in combination with ipilimumab and nivolumab on our clinical trial, NCT04248569. Our studies provide a framework to identify these responses in peripheral blood samples from treated patients and thereby determine correlates of response to therapy. Additionally, the defined fusion-specific TCRs show potential for translation to cellular therapies for FLC, highlighting multiple immunotherapeutic strategies that could benefit FLC patients."

IO biomarker • Hepatocellular Cancer • Oncology • CD4 • DNAJB1 • IFNG • PRKACA