DeCure's autonomous Cancer AI scientist is researching a drug-repurposing hypothesis for Fibrolamellar Carcinoma — screening already-approved drugs against its 18-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleFibrolamellar Carcinoma maps to a 18-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for fibrolamellar carcinoma is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
Cbl proto-oncogene B (CBLB) — CBLB is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 4-methyl-1,2,4-triazol-3-yldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8QTG · 1.419 Å · ligand 3-[3-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]phenyl]-5-(trifluoromethyl)-1~{H}-pyridin-2-one (WUQ). Experimental structure, not a prediction.
What the evidence adds up to
Fibrolamellar carcinoma is a rare primary liver cancer that occurs mostly in children and young adults, with no known cause and no link to chronic liver disease or cirrhosis. The most important prognostic factor is whether the tumour can be surgically removed. A 1995 study of 10 patients found that 70% had metastatic lymphadenopathy at presentation, and all seven patients who had a resection with curative intent later showed recurrent tumour on imaging. Five of those patients died after a mean survival of 9 months. A 2012 review confirmed that the tumours lack mutations in TP53 and CTNNB1, the genes commonly mutated in typical hepatocellular carcinoma, and that their molecular abnormalities were not yet known.
A 2015 study of 19 fibrolamellar carcinoma specimens found that all carried the DNAJB1-PRKACA fusion transcript. FGFR1 protein expression was absent or weak in all cases, and FGFR2 rearrangement was not detected. The authors concluded that these findings reduce the likelihood that FGFR inhibitors would be effective in most patients. In a 2020 phase II trial of the Aurora kinase A inhibitor ENMD-2076, 35 patients were treated. One patient (3%) had a partial response, 57% had stable disease, and median progression-free survival was 3.9 months. The authors stated the results do not support further evaluation of ENMD-2076 as a single agent.
A 2021 retrospective report described 14 evaluable patients treated with triple immunochemotherapy (5-fluorouracil, interferon, and nivolumab). Median progression-free survival was 9 months, 29% longer than before treatment. Five patients achieved clinical remission, and overall objective response was 50%. Two patients withdrew because of side effects. The authors called the regimen promising but noted that further longitudinal data are needed. A 2023 review summarised that surgery remains the only definitive option, and that radiation and chemotherapy have not significantly improved overall survival.
What is still missing are prospective, randomised trials with sufficient patient numbers, given the rarity of the disease. No systemic therapy has been proven to extend survival in a controlled setting. The molecular target DNAJB1-PRKACA has not yet been directly drugged in a successful clinical trial, and patient stratification by fusion status or other biomarkers has not been tested in a randomised design. Funding for multi-centre trials and development of agents that target the fusion protein itself remain absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Scientifica · 2012 · 114 citations · open access
Fibrolamellar Carcinoma: 2012 Update
AbstractFibrolamellar carcinomas are a unique type of primary liver cancer. They occur most commonly in children and young adults. Their etiology remains a mystery, as they are not associated with chronic liver disease. Fibrolamellar carcinomas are not indolent tumors, but have an overall better prognosis than typical hepatocellular carcinomas, in part because of the younger age at presentation and the lack of cirrhosis. The most important prognostic feature is whether the tumor is resectable. Histologically, the tumor is made up of large cells that contain abundant mitochondria. The nuclei of the tumor cells have prominent nucleoli. The tumor cells induce the formation of extensive intratumoral fibrosis, which often grows in parallel, or lamellar bands. The tumor cells clearly show hepatocellular features but are also unique in showing both biliary and neuroendocrine differentiation. The uniqueness of fibrolamellar carcinoma extends to their molecular findings. While the genetic abnormalities that lead to fibrolamellar carcinomas are not yet known, studies have shown that they lack mutations in the genes most commonly mutated in typical hepatocellular carcinoma (TP53 and CTNNB1). In this paper, the clinical, pathological, and basic science literature on fibrolamellar carcinoma is comprehensively reviewed. Key areas of needed research are also discussed.
American Journal of Roentgenology · 1995 · 82 citations
Fibrolamellar hepatocellular carcinoma: stage at presentation and results of aggressive surgical management.
AbstractOBJECTIVE: The purpose of this study was to report the stage of fibrolamellar carcinoma at presentation and the imaging findings of postoperative recurrent tumor in an aggressively managed population and to assess the implications of those findings relative to the patients' management. MATERIALS AND METHODS: Imaging studies in 10 patients with pathologically proved fibrolamellar carcinoma were reviewed. Preoperative studies included CT (n = 10), sonography (n = 8), and MR imaging (n = 2). Postoperative studies included CT (n = 9), sonography (n = 4), and MR imaging (n = 1). Imaging findings were correlated with clinical and surgical follow-up data. Patients were followed up for 2-75 months (median, 26 months). RESULTS: At presentation, seven (70%) of 10 patients had metastatic lymphadenopathy. Seven patients (70%), including four with lymph node metastasis, had tumor resections with intent to cure. Postoperative imaging studies revealed recurrent tumor in all seven of these patients, including six patients (86%) who had intrahepatic recurrence with or without lymph node metastasis after 6-18 months, and one patient (14%) who had distant metastases 66 months postoperatively. Recurrent lesions were subsequently resected in three (43%) of seven patients, who were disease-free at a mean of 8 months after their second resection. Five patients died after 9 months mean survival, and two patients were alive with residual tumor after 3 months mean follow-up. CONCLUSION: Fibrolamellar carcinomas are often of advanced stage at diagnosis. Recurrence after resection with intent to cure is common. Early and frequent follow-up imaging is necessary for optimizing surgical management in patients with fibrolamellar carcinoma.
Journal of Hepatocellular Carcinoma · 2015 · 60 citations · open access
Fibrolamellar hepatocellular carcinoma: current clinical perspectives
AbstractFibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC), which comprises ∼1%-9% of all HCCs. Although FLC is a variant of HCC, it is distinct from HCC in that it most often affects younger patients (10-35 years of age) with no underlying liver disease. FLC often presents with vague abdominal pain, nausea, abdominal fullness, malaise, and weight loss. Surgery is the current mainstay of treatment for FLC and remains the only potentially curative option. While FLCs are considered less responsive to chemotherapy than their classic HCC counterparts, there have been suggestions that multimodality treatments may be effective, especially in advanced cases. Further research is necessary to determine effective systemic therapies as an adjunct to surgery for FLC.
The Oncologist · 2020 · 45 citations · open access
Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma
AbstractLESSONS LEARNED: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. BACKGROUND: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. METHODS: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study. RESULTS: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076. CONCLUSION: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.
Early Experiences with Triple Immunochemotherapy in Adolescents and Young Adults with High-Risk Fibrolamellar Carcinoma
AbstractINTRODUCTION: There are no standard systemic therapies for the treatment of fibrolamellar carcinoma (FLC), as surgery remains the only definitive option. We share our experiences using systemic "triple therapy" (TT) with 5-fluorouracil, interferon, and nivolumab for the treatment of relapsed, refractory, metastatic, or unresectable FLC. METHODS: Data from all patients who received TT from May 2018 to July 2020 were reviewed to assess response, survival, and toxicity. RESULTS: A total of 22 patients were treated with TT, of which 14 (median age of 21 years) were evaluable. They received a median of 18 cycles (8-44). At the time of analysis, the median progression-free survival was 9 months (4.5-26), 29% longer than prior to TT, with 5 patients achieving clinical remission, 8 patients stable or improving, and 1 progression. Overall objective response (clinical remission + partial response) was 50% and tumor control rate (clinical remission + partial response + stable disease) was 93%. Two patients withdrew from treatment due to side effects. DISCUSSION/CONCLUSION: Our early results support TT as a promising medical option to slow disease progression and prolong survival in high-risk patients with FLC. TT can be administered in the outpatient setting and has shown good tolerability. Further longitudinal data is needed to confirm outcomes, especially in patients still early in their treatment.
Journal of Hepatocellular Carcinoma · 2023 · 18 citations · open access
Current Advances in the Treatment of Fibrolamellar Carcinoma of Liver
AbstractFibrolamellar carcinoma (FLC) of the liver is a rare type of liver cancer that is prevalent in children and young adults, often less than 40 years old. The etiology is unclear. It presents without underlying liver disease with distinctive histological features such as fibrous collagen bands surrounding the tumor cells. Fusion protein DNAJB1-PRKACA is found in most of the cases. The prognosis of FLC is poor. Even though curative treatment option is surgery for a certain patient population, other treatment modalities including radiation, chemotherapy are currently being used without significant improvement of overall survival. 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.
<i><scp>FGFR</scp>1</i> and <i><scp>FGFR</scp>2</i> in fibrolamellar carcinoma
AbstractAIMS: Fibrolamellar carcinoma is characterized by a recurrent DNAJB1-PRKACA chimeric transcript. The functional properties of the fusion are unknown, but are believed to include PRKACA up-regulation. PRKCA is a subunit of protein kinase A. The downstream targets of protein kinase A are unknown, but may include interactions with fibroblast growth factor receptor (FGFR) pathways. In addition, inhibitors for FGFR proteins have been developed recently. METHODS AND RESULTS: Nineteen histologically confirmed fibrolamellar carcinomas were studied. All showed the characteristic DNAJB1-PRKACA transcript by reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemistry for FGFR1 was negative in 19 of 19 cases using a monoclonal antibody, while a polyclonal antibody showed no expression (n = 11) or weak and focal expression (n = 8). RNAin-situ hybridization was 2+ in two cases, 1+ in four cases and negative in four cases. FGFR1 fluorescence in-situ hybridization (FISH) revealed polysomy of chromosome 8 in 17 of 19 cases. Break-apart FISH for FGFR2 was negative for rearrangements in 12 of 12 informative cases. CONCLUSIONS: Fibrolamellar carcinomas show polysomy of chromosome 8 and the FGFR1 locus, and only modest mRNA expression and weak or absent expression at the protein level. FGFR2 rearrangement was not detected. These data reduce the likelihood that FGFR inhibitors will be effective in the treatment of most fibrolamellar carcinomas.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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