mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation?

Duvoux, Christophe; Toso, Christian

doi:10.1016/j.trre.2015.02.003

Cited by 63 publications

(48 citation statements)

References 82 publications

(124 reference statements)

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“…hMet activation also led to mTOR activation, which was determined by the presence of p‐AKT, p‐mTOR, and p‐4E‐BP1. Indeed, mTOR activation has been observed in HCC cases and its inhibition discussed for therapy . What was most intriguing was the extent of overlap of gene expression between human HCC displaying hMet activation and mutant β‐catenin signature and our mouse model.…”

Section: Discussionmentioning

confidence: 97%

Modeling a human hepatocellular carcinoma subset in mice through coexpression of met and point‐mutant β‐catenin

et al. 2016

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Hepatocellular cancer (HCC) remains a significant therapeutic challenge due to poorly understood molecular basis. In the current study, we investigate two independent cohorts of 249 and 194 HCC cases for any combinatorial molecular aberrations. Specifically we assessed for simultaneous HMET expression or hMet activation and CTNNB1 mutations to address any concomitant Met and Wnt signaling. To investigate cooperation in tumorigenesis, we co-expressed hMet and β-catenin point-mutants (S33Y or S45Y) in hepatocytes using sleeping beauty (SB) transposon/transposase and hydrodynamic tail vein injection and characterized tumors for growth, signaling, gene signatures and similarity to human HCC. Missense mutations in exon-3 of CTNNB1 were identified in subsets of HCC patients. Irrespective of amino acid affected, all exon-3 mutations induced similar changes in gene expression. Concomitant HMET overexpression or hMet activation, and CTNNB1 mutations, were evident in 9-12.5% of HCCs. Co-expression of hMet and mutant-β-catenin led to notable HCC in mice. Tumors showed active Wnt and hMet signaling with evidence of glutamine synthetase and cyclin-D1 positivity and MAPK/ERK, AKT/Ras/mTOR activation. Introduction of dominant-negative TCF4 prevented tumorigenesis. The gene expression of mouse tumors in hMet-mutant-β-catenin showed high correlation with subsets of human HCC displaying concomitant hMet activation signature and CTNNB1 mutations. In conclusion, we have identified co-operation of hMet and β-catenin activation in a subset of HCC patients and modeled this human disease in mice with a significant transcriptomic intersection. This model will provide novel insight into the biology of this tumor and allow us to evaluate novel therapies as a step towards precision medicine.

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Section: Discussionmentioning

confidence: 97%

Modeling a human hepatocellular carcinoma subset in mice through coexpression of met and point‐mutant β‐catenin

et al. 2016

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“…Extensive preclinical data have pointed to an antitumor effect for mTOR inhibition in HCC [74], and a systematic review of 42 clinical studies involving 3,666 patients receiving a liver transplant for HCC found mTOR inhibition to be associated with a significantly lower rate of HCC recurrence versus CNI therapy (8% versus 13.8%, p < 0.001) [75]. This advantage difference was observed despite a lower proportion of HCC within Milan criteria, and a higher rate of microvascular invasions, in the everolimus-treated group.…”

Section: Liver Transplantationmentioning

confidence: 99%

Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update

Holdaas

Simone

Zuckermann

2016

Journal of Transplantation

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Malignancy after solid organ transplantation remains a major cause of posttransplant mortality. The mammalian target of rapamycin (mTOR) inhibitor class of immunosuppressants exerts various antioncogenic effects, and the mTOR inhibitor everolimus is licensed for the treatment of several solid cancers. In kidney transplantation, evidence from registry studies indicates a lower rate of de novo malignancy under mTOR inhibition, with some potentially supportive data from randomized trials of everolimus. Case reports and small single-center series have suggested that switch to everolimus may be beneficial following diagnosis of posttransplant malignancy, particularly for Kaposi's sarcoma and nonmelanoma skin cancer, but prospective studies are lacking. A systematic review has shown mTOR inhibition to be associated with a significantly lower rate of hepatocellular carcinoma (HCC) recurrence versus standard calcineurin inhibitor therapy. One meta-analysis has concluded that patients with nontransplant HCC experience a low but significant survival benefit under everolimus monotherapy, so far unconfirmed in a transplant population. Data are limited in heart transplantation, although observational data and case reports have indicated that introduction of everolimus is helpful in reducing the recurrence of skin cancers. Overall, it can be concluded that, in certain settings, everolimus appears a promising option to lessen the toll of posttransplant malignancy.

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“…Additionally, everolimus was approved by FDA as immunosuppression agent in 2013, and considering patients included in the current study were from 2006 to 2012, everolimus was not used as immunosuppression in these patients prior to their HCC recurrence. Since 2015, we have been utilizing everolimus in all HCC patients with high‐risk features in the explant in addition sorafenib, which could potentially impact the recurrence rates and survival outcomes; this will be analyzed as we accrue patients and follow‐up time from the current cohort. In the current study, only 3 OLT recipients received rapamycin as their primary immunosuppression after OLT, while none of the patients in the cohort received everolimus.…”

Section: Discussionmentioning

confidence: 99%

No apparent benefit of preemptive sorafenib therapy in liver transplant recipients with advanced hepatocellular carcinoma on explant

Das

Koçak

Helmick

et al. 2018

Clinical Transplantation

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mTOR inhibitor therapy: Does it prevent HCC recurrence after liver transplantation?

Cited by 63 publications

References 82 publications

Modeling a human hepatocellular carcinoma subset in mice through coexpression of met and point‐mutant β‐catenin

Modeling a human hepatocellular carcinoma subset in mice through coexpression of met and point‐mutant β‐catenin

Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update

No apparent benefit of preemptive sorafenib therapy in liver transplant recipients with advanced hepatocellular carcinoma on explant

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