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Jul 7, 2010 - p70S6K, a direct downstream target of mTOR [7,8]. .... mTOR, mammalian target of rapamycin; ATG, autophagy-related genes; p70S6K;.

International Hepatology

Inhibition of mammalian target of rapamycin: Two goals with one shot? Christopher Soll, Pierre-Alain Clavien* Swiss Hepato-Pancreato-Biliary (HPB) & Transplantation Center, Department of Surgery, University Hospital Zürich, Switzerland

COMMENTARY ON: Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Toso C, Merani S, Bigam DL, Shapiro AM, Kneteman NM. Hepatology, 2010 Apr;51(4):1237–1243. http://www.ncbi.nlm.nih.gov/pubmed/20187107 Ó 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Serious complications of any immunosuppressive regimen after transplantation are either recurrent or de novo malignancies [1]. After orthotopic liver transplantation (OLT), performed on patients presenting with hepatocellular carcinoma (HCC), recurrent malignancy occurs between 3% and up to 52%, depending on the stage of the disease at the time of OLT. The majority of recurrent carcinomas are detected more than one year after OLT with a median survival of less than 10 months following the diagnosis of the recurrence [2]. Therapeutic options are limited and the prognosis is poor for these recurrences even after liver resection [3] and re-transplantation [4]. Rapamycin, which was discovered in 1965 on the Easter Islands (Rapa Nui) from soil samples, belongs to a new class of immunosuppressive drugs. Drugs like sirolimus, also known as rapamycin (RapamuneÒ, Wyeth) or everolimus (CerticanÒ, Novartis) belong to inhibitors of the mammalian target of rapamycin (mTOR) and simultaneously exhibit anti-proliferative and immunosuppressive effects [5]. This protein is a central regulator of cell metabolism, proliferation, and survival. It also modulates the innate and adaptive immune responses by the regulation of dendritic and T-cells [6] (Fig. 1). These drugs could efficiently achieve two goals at once: inducing tolerance of the graft and reducing the risk of cancer. Recent data from in vitro and in vivo studies suggest an import role of mTOR in HCC. Approximately 30–50% of patients with HCC exhibit an activation of the mTOR pathway as assessed by immunohistochemical analysis of phosphorylated p70S6K, a direct downstream target of mTOR [7,8]. A tempting

Received 7 July 2010; received in revised form 15 July 2010; accepted 16 July 2010 * Corresponding author. Address: Swiss Hepato-Pancreato-Biliary (HPB) Center, Department of Surgery, University Hospital Zürich, Raemistrasse 100, 8091 Zürich, Switzerland. Tel.: +41 44 255 33 00; fax: +41 44 255 44 49. E-mail address: [email protected] (P.-A. Clavien).

strategy could be to use mTOR-inhibitors as first-line immunosuppression in the setting of OLT for HCC. Different studies have demonstrated better survival rates in patients on sirolimus as compared to control liver recipients [9]. The significance of these studies remains limited due to the small number of patients included and the retrospective study design. Toso, Kneteman, and colleagues [10] analyzed the impact of different immunosuppressive regimens on the long-term survival of recipients originally presenting with HCC. They included 2491 recipients originally presenting with HCC and a control group of 12,167 patients including those transplanted for diseases other than HCC. The data were taken from the Scientific Registry of Transplant Recipients (SRTR) database, which offers information about all candidates listed for OLT, donors, and recipients in the United States of America (www.ustransplant.org). In the HCC-group, 109 patients treated with sirolimus were compared to 2382 patients treated with a different immunosuppressive protocol. Patients displaying stable immunosuppression for at least 6 months post-transplant were included in the univariate and multivariate analysis. The two groups of patients with HCC on and off sirolimus were comparable. The patients on sirolimus revealed an even higher MELD score before OLT, excluding the risk of a confounding bias based on a post-transplant kidney function. In this study, the 5-year survival of OLT recipients presenting with HCC was 83% when receiving sirolimus compared to 69% in those patients treated with another regimen (HR 0.53, 95% CI: 0.31–0.92; p 60.05). An improvement of almost 15% in the 5-year survival in patients treated with an mTOR-inhibition regimen is impressive and potentially of high clinical relevance. However, some questions arise when interpreting the data of this retrospective study. What was the proportion of patients meeting the Milan criteria? Was disease comparable regarding tumour classification? Both the univariate and multivariate analysis may be easily confounded by more aggressive tumour biology in the HCC-group that had not received sirolimus. Several studies have shown that tumour staging as well as grading and vascular invasion are the most important factors affecting tumour recurrence in patients receiving OLT for HCC [2,4]. Unfortunately, the study does not provide this important information. What was the recurrence rate in HCC-groups after OLT? Although inhibition of mTOR prevents tumour recurrence in in vitro and in vivo models [7], the present data do not demonstrate that sirolimus-based immunosuppression improves survival due to anti-cancer effects. The study did not assess the main outcome of interest, the recurrence-free survival, as the focus was on overall

Journal of Hepatology 2011 vol. 54 j 182–183

JOURNAL OF HEPATOLOGY A

B

Growth factors

T-cell receptor

TK-receptor

Somatic cell e.g. hepatocyte

PI3K

T-Lymphocyte

PH Akt

ATG proteins Autophagy

p70S6K

4E-BP1

Protein Synthesis and Cell Growth

HIF-1

PH Akt

mTOR

Sirolimus Everolimus

mTOR

PI3K

Sirolimus Everolimus nucleus

NF-κB

Expression of cell cycle progression genes, IL2 and IL-2R

Angiogenesis

Fig. 1. Two different cell types affected by one drug. (A) Growth factors (e.g. insulin) usually activate tyrosine kinase receptors in the cells. This leads to the activation of the PI3K-AKT-mTOR pathway. mTOR, in turn, regulates cellular processes like autophagy, cell growth, and angiogenesis, via further downstream targets. These cellular functions are potentially disturbed in tumourgenesis and tumour progression. (B) In T-cells, the activation of the T-cell receptor leads to an mTOR-mediated cell cycle progression and increased expression of IL2 and the IL2-receptor, leading to cell mediated immune-response. Drugs like sirolimus or everolimus inhibit this pathway at the level of mTOR and may inhibit both the tumour cell growth and immune-response at once. (Simplified overview, for details see Thomson et al. [6].) Abbreviations: TKreceptor, tyrosine-kinase receptor; PI3K, phosphoinositide-3 kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; ATG, autophagy-related genes; p70S6K; ribosomal protein S6 kinase; 4E-BP1, 4E-binding protein 1; HIF-1, hypoxia-inducible factor 1; NF-jB, nuclear factor ’kappa-light-chain-enhancer’ of activated B-cells; IL2, Interleukin 2, IL2-R, Interleukin 2 receptor.

survival. There is also no information about the median follow-up after OLT. Therefore, the SRTR data may underestimate the HCC recurrence rate due to under-reporting. In addition, the unknown median follow-up limits the tempting conclusion that sirolimus has oncological benefits in the HCC population. Is it possible to break the paradigm of effectively preventing rejection with an immunosuppressive regimen and its inherent risk of new or recurrent tumours? Toso and colleagues could not answer this question conclusively, but they did provide important clinical information about a representative and large cohort of patients after OLT. These data are of great value to design definitive, randomized controlled trials testing sirolimus in the HCC and nonHCC population and may provide the final answer. Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References

[2] Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10 (1):35–43. [3] Schwartz M, Roayaie S, Llovet J. How should patients with hepatocellular carcinoma recurrence after liver transplantation be treated? J Hepatol 2005;43 (4):584–589. [4] Schlitt HJ, Neipp M, Weimann A, Oldhafer KJ, Schmoll E, Boeker K, et al. Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncol 1999;17 (1):324–331. [5] Monaco AP. The role of mTOR inhibitors in the management of posttransplant malignancy. Transplantation 2009;87 (2):157–163. [6] Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 2009;9 (5):324–337. [7] Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008;135 (6):1972–1983, [1983:e1971–1911]. [8] Soll C, Jang JH, Riener MO, Moritz W, Wild PJ, Graf R, et al. Serotonin promotes tumor growth in human hepatocellular cancer. Hepatology (Baltimore, Md) 2010;51 (4):1244–1254. [9] Zimmerman MA, Trotter JF, Wachs M, Bak T, Campsen J, Skibba A, et al. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver transpl 2008;14 (5):633–638. [10] Toso C, Merani S, Bigam DL, Shapiro AM, Kneteman NM. Sirolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology (Baltimore, Md) 2010;51 (4):1237–1243.

[1] Sanchez W, Talwalkar JA, Gores GJ. Will all liver transplantation patients eventually die from cancer? J Hepatol 2006;44 (1):13–18.

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