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Ref Type Journal Article
PMID (20347502)
Authors Bhoori S, Toffanin S, Sposito C, Germini A, Pellegrinelli A, Lampis A, Mazzaferro V
Title Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle.
Abstract Text The advent of molecular medicine that targets specific pathways is changing the therapeutic approach to hepatocellular carcinoma. For several aberrantly activated pathways in hepatocarcinoma, surrogate markers of activation can be assessed by immunohistochemistry, although associations with in vivo response to targeted therapies are still lacking.A patient, who presented with hepatic and extra-hepatic hepatocarcinoma recurrence 11 years after liver transplantation, was assessed for beta-catenin, pERK, and pS6 in primary and secondary tumor specimens, in order to define a possible activation of the Wnt, Ras/MAPK and Akt/mTOR pathways and design a personalized targeted therapy in absence of alternative treatment options. Moreover, mutation analysis of the beta-catenin gene (CTNNB1) and DNA microsatellite analyses were performed.The identification of the same mutation in the beta-catenin gene, as well as the same microsatellite pattern in tumor tissues taken 11 years apart, proved that the observed hepatocarcinoma was a true recurrence. Nuclear beta-catenin and pS6 in tumor cells were positive, whereas pERK was positive only in the peritumoral endothelium. This pattern of immunohistochemistry, after failure of sorafenib alone, lead to the choice to add the mTOR inhibitor, everolimus, to sorafenib. Three months later a 50% tumor reduction was observed, and after 6 months a further reduction of tumor vital components was confirmed, while a grade II gastrointestinal bleeding episode occurred.A personalized approach aimed to treat recurrent hepatocarcinoma is possible through analysis of tumoral molecular pathways. Partial success of the selected combination of sorafenib and everolimus supports the pivotal role of mTOR signalling and highlights the importance of reliable biomarkers to route the best molecular-based therapeutic options in HCC.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CTNNB1 G34R hepatocellular carcinoma predicted - sensitive Everolimus + Sorafenib Case Reports/Case Series Actionable In a clinical case study, Afinitor (everolimus) and Nexavar (sorafenib) combination therapy resulted in a 50% tumor response after 3 months of treatment in a patient with metastatic hepatocellular carcinoma harboring CTNNB1 G34R whose disease progressed on prior Nexavar (sorafenib) monotherapy, and the response was ongoing at 8 months (PMID: 20347502). 20347502