Current and Future Treatment Strategies for Patients with Advanced Hepatocellular Carcinoma: Role of mTOR Inhibition

Abstract

Hepatocellular carcinoma (HCC) is a common cancer that has the third highest cancer-related mortality rate worldwide. Although potentially curable by transplantation if detected early, the majority of cases are diagnosed at an advanced stage of disease for which limited treatment options are available. The only proven systemic therapy for advanced HCC is sorafenib, a multi-kinase inhibitor that has demonstrated modest efficacy and reasonable tolerability in patients with advanced HCC. Five years after the approval of sorafenib, no other agent has been proven to be beneficial in the first- or second-line setting in advanced HCC. While molecular studies have highlighted various potential targets in HCC, the mammalian target of rapamycin (mTOR) has emerged as an exciting target for cancer therapy including HCC. Laboratory data have linked the phosphatidylinositol 3-kinase/AKT/mTOR axis to various oncogenic processes, including survival and angiogenesis. Historically, mTOR inhibitors have been used for their immunosuppressive properties, but more recently they have been approved as anticancer agents. Retrospective HCC studies suggest that the inclusion of mTOR inhibition as part of an immunosuppressant regimen after transplantation may reduce HCC recurrence compared with other immunosuppressive agents such as calcineurin inhibitors. More recently, single-arm, phase I/II studies have shown that mTOR inhibitors also have activity as monotherapy in cases of recurrent HCC or de novo advanced HCC. This article will review the rationale for targeting the mTOR pathway in HCC, and the currently available clinical data supporting its development for HCC.

DEPTOR Expression Negatively Correlates with mTORC1 Activity and Tumor Progression in Colorectal Cancer

“…It was recently demonstrated that mTOR inhibitors have anti-tumor effects (Bijnsdorp et al, 2011;Finn., 2012;Migliardi et al, 2012). However, our study failed to determine the relationship between the expression of P-S6 (S235/236), DEPTOR and overall survival in CRC.…”

Review on immunosuppression in liver transplantation

“…mTOR signaling plays a role in tumor angiogenesis and proliferation that is important in carcinogenesis of HCC [70] . In LT for HCC, sirolimus based immunosuppression was reported to be associated with lower tumor recurrence rate, longer recurrencefree survival and overall survival, and lower recurrencerelated mortality compared with CNIs [71] .…”

Successful Cessation of Progression of Hepatocellular Carcinoma with Everolimus Therapy

“…Everolimus, the only oral, mTOR inhibitor has established efficacy in advanced renal cell carcinoma, advanced neuroendocrine tumours and hormone receptor positive/human epidermal growth factor receptor-2 negative advanced breast cancer [3]. mTOR inhibition with everolimus, both in vitro (Human HCC cell lines) and in vivo (murine xenograft model) was documented to reduce tumor growth and increase survival.…”

“…Everolimus is the orally active mTOR inhibitor approved in anticancer applications and could be a potential option for advanced HCC treatment [3,5]. Here we report a case of successful cessation of advanced, unresectable HCC progression with the continued therapy of everolimus.…”

“…Consequently, sorafenib got approved as the first systemic agent for advanced HCC. However, poor tolerability and response confine the application of sorafenib in advance HCC management [3]. PI3K/AKT/mTOR signalling pathway has a vital role in cell proliferation, migration, survival and angiogenesis and can prove to be an encouraging target.…”