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DRUG:

DNAJB1-PRKACA peptide vaccine

i
Other names: DNAJB1-PRKACA peptide vaccine
Associations
Company:
BMS, Sidney Kimmel Comprehensive Cancer Center
Drug class:
Immunostimulant
Related drugs:
Associations
2ms
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
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STK11 (Serine/threonine kinase 11) • GNAS (GNAS Complex Locus) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
7ms
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)
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).
P1 data • Journal • Checkpoint inhibition
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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Tecentriq (atezolizumab) • DNAJB1-PRKACA peptide vaccine • Fusion-VAC-XS15
8ms
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.
Journal • IO biomarker
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CD8 (cluster of differentiation 8) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
8ms
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
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha) • LINC00473 (Long Intergenic Non-Protein Coding RNA 473)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
10ms
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
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TMB (Tumor Mutational Burden) • NRAS (Neuroblastoma RAS viral oncogene homolog) • FGFR3 (Fibroblast growth factor receptor 3) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • GNAS (GNAS Complex Locus) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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NRAS mutation • CTNNB1 mutation • DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
11ms
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)
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
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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Imfinzi (durvalumab) • sirpiglenastat (DRP-104) • DNAJB1-PRKACA peptide vaccine
11ms
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)
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.
Clinical • P1 data • Checkpoint inhibition
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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Tecentriq (atezolizumab) • DNAJB1-PRKACA peptide vaccine • Fusion-VAC-XS15
12ms
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
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
1year
Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases. (PubMed, J Nat Prod)
The DNAJB1-PRKACA oncogenic gene fusion results in an active kinase enzyme, J-PKAcα, that has been identified as an attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC)...Human kinome profiling of 1 against a panel of 370 kinases revealed potent inhibition of select serine/threonine kinases in the CLK and PKG families with IC values in the range ∼11-90 nM. An efficient, four-step total synthesis of 1 has been accomplished, enabling further evaluation of aplithianines as biologically relevant kinase inhibitors.
Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA peptide vaccine
1year
Gene rearrangement and expression of PRKACA and PRKACB governs morpho-biology of pancreatobiliary oncocytic neoplasms. (PubMed, Mod Pathol)
We analyzed PRKACA/B fusion genes including ATP1B1-PRKACA, DNAJB1-PRKACA, and ATP1B1-PRKACB by reverse transcription PCR (RT-PCR); mRNA expression of fusion genes and non-rearranged PRKACA/B genes by quantitative RT-PCR; mutations in KRAS, BRAF, and GNAS by targeted sequencing or droplet digital PCR; and the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA) and beta (PRKACB), phosphorylated-CREB, and aberrations of p16, p53, SMAD4, STK11, and β-catenin by immunohistochemistry...In conclusion, PRKACA/B fusion genes are not only the characteristic drivers of IOPNs, but also play a crucial role in the development of subclonal oncocytic neoplasms. Moreover, oncocytic morphology is strongly associated with upregulation of PRKACA/B, which may provide clues for potential therapeutic options.
Journal
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • STK11 (Serine/threonine kinase 11) • SMAD4 (SMAD family member 4) • CTNNB1 (Catenin (cadherin-associated protein), beta 1) • ATP1B1 (ATPase Na+/K+ transporting subunit beta 1) • GNAS (GNAS Complex Locus) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha) • PRKACB (Protein Kinase CAMP-Activated Catalytic Subunit Beta)
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TP53 mutation • KRAS mutation • BRAF mutation • GNAS mutation
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DNAJB1-PRKACA peptide vaccine
1year
A DNAJB1-PRKACA fusion peptide vaccine combined with ipilimumab and nivolumab elicits polyclonal fusion-specific T cell responses in fibrolamellar carcinoma (SITC 2023)
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.
PD(L)-1 Biomarker • IO biomarker
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IFNG (Interferon, gamma) • CD4 (CD4 Molecule) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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Opdivo (nivolumab) • Yervoy (ipilimumab) • DNAJB1-PRKACA peptide vaccine • Hiltonol (poly-ICLC)
1year
FusionVAC22_01: Fusion Transcript-based Peptide Vaccine Combined With Immune Checkpoint Inhibition (clinicaltrials.gov)
P1, N=20, Recruiting, University Hospital Tuebingen | Not yet recruiting --> Recruiting
Enrollment open • Checkpoint inhibition
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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Tecentriq (atezolizumab) • DNAJB1-PRKACA peptide vaccine • Fusion-VAC-XS15
1year
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 (DGHO 2023)
Most importantly, until now the second patient showed stable disease for 8 months after vaccination. Based on these promising data, we established a Phase I open label, multicentric clinical trial (EU-CT Number 2022-502869-17-00) evaluating the immunogenicity along with safety and toxicity, as well as first signs of efficacy of the FusionVAC-22 based peptide vaccine, combined with an ICI (anti-PD-L1), in 20 patients with locally advanced or metastatic FL-HCC or other malignant disease with proven presence of the DNAJB1-PRKACA fusion transcript.
Clinical • P1 data • Checkpoint inhibition
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine • Fusion-VAC-XS15
1year
A pilot study of a DNAJB1-PRKACA fusion kinase peptide vaccine combined with nivolumab and ipilimumab for patients with fibrolamellar hepatocellular carcinoma (SITC 2023)
FLC-Vac, consisting of a 24 amino acid peptide targeting the DNAJB1-PRKACA fusion with adjuvant poly-ICLC, is administered on weeks 0, 1, 2, 3, 6, 9 during the priming phase of the study and NIVO, 3 mg/kg, followed by IPI, 1 mg/kg, are administered every 3 weeks for 4 doses. Conclusions This first-in human study provides initial evidence of safety and clinical efficacy of a vaccine targeting the DNAJB1-PRKACA fusion plus immune checkpoint inhibitor therapy for FLC. T cell responses are consistent with neoantigen-specific immunity against the DNAJB1-PRKACA chimera.
Clinical
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IFNG (Interferon, gamma) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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Opdivo (nivolumab) • Yervoy (ipilimumab) • DNAJB1-PRKACA peptide vaccine • Hiltonol (poly-ICLC)
1year
Fibrolamellar hepatocellular carcinoma: a case report and gene analysis. (PubMed, Surg Case Rep)
We encountered a case of FL-HCC, a rare hepatic tumor in an adolescent patient, and evaluated the genetic background. Our findings could contribute to the elucidation of the mechanisms underlying carcinogenesis and progression in patients with FL-HCC and thereby contribute to the development of new therapeutic strategies in the future that may improve patient prognosis.
Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA peptide vaccine
1year
Exploring the molecular pathogenesis, diagnosis and treatment of fibrolamellar hepatocellular carcinoma: A state of art review of the current literature. (PubMed, Pathol Res Pract)
In regards to this tumour's genetic analysis, it is characterised by a 400 kb deletion on chromosome 19 leading to a functional DNAJB1-PRKACA chimeric transcript in addition to tetraploidy in 50% of cases...Although the prognosis for FLC is favourable as compared to other hepatic cancer subtypes such as intrahepatic cholangiocarcinoma, there is a high rate of recurrence ranging from 33% to 100% with a median recurrence-free survival of 20-48 months. As a result of this there is a low overall cure rate associated with this tumour type and much more research is required to gain an in-depth understanding of the molecular mechanisms occurring in order to provide more adequate treatment to patients who suffer from this condition.
Review • Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA peptide vaccine
over1year
New P1 trial • Checkpoint inhibition
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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Tecentriq (atezolizumab) • DNAJB1-PRKACA peptide vaccine • Fusion-VAC-XS15
over1year
Current Advances in the Treatment of Fibrolamellar Carcinoma of Liver. (PubMed, J Hepatocell Carcinoma)
Fusion protein DNAJB1-PRKACA is found in most of the cases...Recently, targeted therapy and immunotherapy have been studied which may provide survival advantage in the future. This review sought to compile data from clinical trials and case reports/series to outline the current state of FLC treatment.
Review • Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA peptide vaccine
over1year
Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss. (PubMed, Nat Commun)
In all analyses, DNAJB1-PRKACA organoids presented with milder phenotypes, suggesting differences between FLC genetic backgrounds, or for example the need for additional mutations, interactions with niche cells, or a different cell-of-origin. These engineered human organoid models facilitate the study of FLC.
Journal
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BAP1 (BRCA1 Associated Protein 1) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha) • PRKAR1A (Protein Kinase CAMP-Dependent Type I Regulatory Subunit Alpha)
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BAP1 mutation • DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
over1year
DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma (clinicaltrials.gov)
P1, N=56, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=12 --> 56 | Trial completion date: Mar 2024 --> Mar 2027 | Trial primary completion date: Mar 2024 --> Mar 2027
Enrollment change • Trial completion date • Trial primary completion date
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CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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Opdivo (nivolumab) • Yervoy (ipilimumab) • DNAJB1-PRKACA peptide vaccine • Hiltonol (poly-ICLC)
over1year
DNAJB1-PRKACA fusion in fibrolamellar hepatocellular carcinoma induces glutamine addiction and an immunosuppressive tumor microenvironment (AACR 2023)
Fibrolamellar hepatocellular carcinoma (FLC) is a rare and often lethal form of liver cancer that primarily affects children and young adults. Systemic treatment of BALB/c mice bearing TIBx-FLC tumors with JHU-083, a glutamine antagonist, in combination with immune checkpoint inhibitor therapy enhanced survival as compared to vehicle or monotherapy. These data identify altered glutamine metabolism as a target in FLC, and may provide an explanation for immune suppression seen in the FLC tumor microenvironment.
CD8 (cluster of differentiation 8) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine • JHU083
2years
The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma. (PubMed, Nat Commun)
Vaccine-induced DNAJB1-PRKACA-specific T cell responses persist over time and, in contrast to various previous treatments, are accompanied by durable relapse free survival of the patient for more than 21 months post vaccination. Our preclinical and clinical findings identify the DNAJB1-PRKACA protein as source for immunogenic neoepitopes and corresponding T cell receptors and provide efficacy in a single-patient study of T cell-based immunotherapy specifically targeting this oncogenic fusion.
Journal
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CD8 (cluster of differentiation 8) • CD4 (CD4 Molecule) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
2years
Oncogenic addiction of Fibrolamellar hepatocellular carcinoma to the fusion kinase DNAJB1-PRKACA. (PubMed, Clin Cancer Res)
Our results validate DNAJB1-PRKACA as the oncogene in FLC and demonstrate both a continued requirement for the oncogene for tumor growth as well as an oncogenic addiction that can be exploited for targeted therapies. We anticipate our approach will be useful for investigations of other fusion genes in pediatric cancers and spur development of precision therapies.
Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
over2years
Fibrolamellar hepatocellular carcinoma: A rare but unpleasant event. (PubMed, World J Gastrointest Oncol)
Recent advances in molecular studies of FLC have found a unique DNAJB1-PRKACA fusion transcript in most of the cases studied. The review aims to describe clinical characteristics, diagnostic methods, and therapeutic modalities for this rare tumor to raise awareness among clinicians and surgeons.
Review • Journal
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AFP (Alpha-fetoprotein) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha) • PRKCA (Protein Kinase C Alpha)
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DNAJB1-PRKACA fusion
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DNAJB1-PRKACA peptide vaccine
over2years
Novel protein kinase cAMP-Activated Catalytic Subunit Alpha (PRKACA) inhibitor shows anti-tumor activity in a fibrolamellar hepatocellular carcinoma model. (PubMed, Biochem Biophys Res Commun)
Furthermore, this compound showed anti-tumor activity in an FL-HCC patient-derived xenograft model expressing the DNAJB1-PRKACA fusion gene. Our data suggest that DS89002333 could be considered as a potential therapeutic agent for FL-HCC.
Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha) • PRKCA (Protein Kinase C Alpha)
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DNAJB1-PRKACA peptide vaccine
over2years
The Use of Fluorescence in situ Hybridization to Confirm PRKACA Gene Rearrangement in Fibrolamellar Hepatocellular Carcinoma: A Validation Study. (PubMed, Ann Clin Lab Sci)
This study shows that, using standard techniques, FISH testing with a commercially available break apart probe targeting the PRKACA gene can be used as a surrogate for the DNAJB1-PRKACA fusion commonly found in FL-HCC. Also, the PRKACA gene rearrangement is not expressed in other hepatic neo-plasms/proliferations or extrahepatic neoplasms seen in children and young adults. Finally, FISH testing can be used as a diagnostic tool to confirm the diagnosis of FL-HCC, in the appropriate clinical setting.
Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha) • PRKCA (Protein Kinase C Alpha)
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DNAJB1-PRKACA peptide vaccine
over2years
Multi-omic analysis of microRNA-mediated regulation reveals a proliferative axis involving miR-10b in fibrolamellar carcinoma. (PubMed, JCI Insight)
This functional genomics study highlights a novel proliferative axis in FLC and provides a rich resource for further investigation of the molecular landscape of FLC. The results reveal that miR-10b-5p shapes gene expression and promotes cell proliferation in FLC. Future studies are necessary to identify how the loss of miR-455-3p contributes to FLC progression and how miR-10b-5p may coordinate with miR-455-3p to control tumor phenotypes.
Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha) • PRKCA (Protein Kinase C Alpha) • MIR10B (MicroRNA 10b)
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DNAJB1-PRKACA peptide vaccine
over2years
A framework for fibrolamellar carcinoma research and clinical trials. (PubMed, Nat Rev Gastroenterol Hepatol)
In this Roadmap, we review advances since the seminal discovery in 2014 that nearly all FLC tumours express a signature oncogene (DNAJB1-PRKACA) encoding a fusion protein (DNAJ-PKAc) in which the J-domain of a heat shock protein 40 (HSP40) co-chaperone replaces an amino-terminal segment of the catalytic subunit of the cyclic AMP-dependent protein kinase (PKA). Important gains include increased understanding of oncogenic pathways driven by DNAJ-PKAc; identification of potential therapeutic targets; development of research models; elucidation of immune mechanisms with potential for the development of immunotherapies; and completion of the first multicentre clinical trials of targeted therapy for FLC. In each of these key areas we propose a Roadmap for future progress.
Review • Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKCA (Protein Kinase C Alpha)
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DNAJB1-PRKACA peptide vaccine
over2years
CD8 T cell responses to conserved DNAJB1-PRKACA fusion neoantigens in fibrolamellar carcinoma (IMMUNOLOGY 2022)
Ongoing experiments will test if cells expressing these TCRs can control growth of fusion-expressing tumors in vivo. Together, these studies have defined the first reported fusion-specific T cell response in an FLC patient, as well as fusion-specific TCRs that hold promise for development in adoptive T cell therapies.
IO biomarker
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • IL2 (Interleukin 2) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKACA (Protein Kinase CAMP-Activated Catalytic Subunit Alpha) • PRKCA (Protein Kinase C Alpha)
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DNAJB1-PRKACA peptide vaccine
over2years
Targeting Bcl-xL in fibrolamellar hepatocellular carcinoma (AACR 2022)
FLC is driven by a fusion oncokinase, DNAJB1-PRKACA, that arises from a deletion fusing exon 1 of DNAJB1 and exons 2-10 of PRKACA, the catalytic subunit of protein kinase A. Expression of this chimeric oncokinase is capable of recapitulating the key histologic and transcriptomic features of FLC...Unfortunately, Navitoclax has an on-target and dose-limiting toxicity of thrombocytopenia, which limits its clinical application...In conclusion, TOPO1 and Bcl-xL prove to be promising targets of interest in FLC. Targeting both with DT2216 and irinotecan leads to tumor shrinkage in pre-clinical models and offer a potential therapeutic/pharmacological intervention for FLC.
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKCA (Protein Kinase C Alpha)
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irinotecan • navitoclax (ABT 263) • DT2216 • DNAJB1-PRKACA peptide vaccine
over2years
The oncogenic fusion protein DNAJB1-PRKACA can be actively targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma (AACR 2022)
DNAJB1-PRKACA-specific T cells persisted in peripheral blood and were accompanied by relapse free survival of the patient until now, more than one year post vaccination. These findings identified the DNAJB1-PRKACA fusion transcript as novel prime source for broadly applicable neoepitopes and corresponding TCRs and provide first evidence for their application in cancer immunotherapy of FL-HCC.
IO biomarker
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • CD4 (CD4 Molecule) • LAMP1 (Lysosomal Associated Membrane Protein 1) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKCA (Protein Kinase C Alpha)
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IFNG expression
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DNAJB1-PRKACA peptide vaccine
over2years
Characterization of CD8 T cell responses to DNAJB1-PRKACA fusion neoantigens in fibrolamellar carcinoma (AACR 2022)
Collectively, these studies have defined the first reported fusion-specific T cell response in FLC, as well as fusion-specific TCRs that hold promise for use in adoptive T cell therapies. Our spatial transcriptomic analyses have also begun to illuminate the immune microenvironment in FLC and will inform future efforts to develop immunotherapies for this disease.
IO biomarker
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKCA (Protein Kinase C Alpha)
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DNAJB1-PRKACA peptide vaccine
over2years
DNAJB1-PRKACA in HEK293T cells induces LINC00473 overexpression that depends on PKA signaling. (PubMed, PLoS One)
LINC00473 overexpression was reversible with siRNA targeting of PRKACA as well as pharmacologic targeting of PKA and Hsp40 in HEK-DP cells. Therefore, our model suggests that LINC00473 is a candidate marker for DP activity.
Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKCA (Protein Kinase C Alpha) • LINC00473 (Long Intergenic Non-Protein Coding RNA 473)
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DNAJB1-PRKACA peptide vaccine
3years
Integrated Phosphoproteomics for Identifying Substrates of Human Protein Kinase A (PRKACA) and Its Oncogenic Mutant DNAJB1-PRKACA. (PubMed, J Proteome Res)
We also treated cells with PKA inhibitors that function by two different mechanisms (rpcAMPs and PKI) and examined phosphoproteome profiles, finding some substrates that persisted in the presence of inhibitors and revealing differences between WT and chimera. Overall, these results provide potential insights into J-PKA's oncogenic activity in a complex cellular system and may provide candidate targets for therapeutic follow-up.
Journal
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DNAJB1 (DnaJ Heat Shock Protein Family (Hsp40) Member B1) • PRKCA (Protein Kinase C Alpha)
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DNAJB1-PRKACA peptide vaccine