Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates

Kelley, Robin Kate; Nimeiri, Halla; Munster, P.N.; Vergo, Maxwell T.; Huang, Yande; Li, C.-M.; Hwang, Jimmy J.; Mulcahy, Mary F.; Yeh, Benjamin M.; Kühn, Peter; Luttgen, Madelyn; Grabowsky, Jennifer A.; Stucky-Marshall, Lisa; Korn, W. Michael; Ko, Andrew H.; Bergsland, Emily K.; Benson, Al B.; Venook, Alan P.

doi:10.1093/annonc/mdt109

Cited by 52 publications

(45 citation statements)

References 38 publications

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“…The median overall survival was 19.3 mo (95%CI: 13.4-25.1 mo), and the median time to progression was 6.77 mo (95%CI: 2.3-11.1 mo). Although a few studies have shown that there is some evidence of synergistic anticancer activity, early-phase clinical studies of mTOR inhibitors plus sorafenib for advanced HCC reported ambivalent findings, which were the results of increased toxicity (e.g., hand-foot syndrome) in combination therapy [51,52] . In a recent study from Italy, the outcomes of sorafenib treatment for post-LT HCC recurrence were significantly better than those of best medical care [median patient survival from recurrence: 21.3 mo vs 11.8 mo, hazard ratio (HR) = 5.2, P = 0.0009; median patient survival from untreatable presentation or progression: 10.6 mo vs 2.2 mo, HR = 21.1, P < an overall survival rate of 90% at a median follow-up period of 275 d (range: 32-677 d) [33] .…”

Section: Treatment For Multiple Recurrencementioning

confidence: 99%

Management of recurrent hepatocellular carcinoma after liver transplant

Chok¹

2015

WJH

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Hepatocellular carcinoma (HCC) is the leading cause of deaths in patients with hepatitis B or C, and its incidence has increased considerably over the past decade and is still on the rise. Liver transplantation (LT) provides the best chance of cure for patients with HCC and liver cirrhosis. With the implementation of the MELD exception system for patients with HCC waitlisted for LT, the number of recipients of LT is increasing, so is the number of patients who have recurrence of HCC after LT. Treatments for intrahepatic recurrence after transplantation and after other kinds of surgery are more or less the same, but long-term cure of posttransplant recurrence is rarely seen as it is a "systemic" disease. Nonetheless, surgical resection has been shown to be effective in prolonging patient survival despite the technical difficulty in resecting graft livers. Besides surgical resection, different kinds of treatment are also in use, including transarterial chemoembolization, radiofrequency ablation, highintensity focused ultrasound ablation, and stereotactic body radiation therapy. Targeted therapy and modulation of immunosuppressants are also adopted to treat the deadly disease.

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Section: Treatment For Multiple Recurrencementioning

confidence: 99%

Management of recurrent hepatocellular carcinoma after liver transplant

Chok¹

2015

WJH

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“…Similarly, an incremental activation of mTOR was detected in HCC, dysplastic nodules and non-neoplastic surrounding tissues when compared with normal livers, with the highest expression being in HCC [57,58]. In HCCs, activation of the mTOR signaling has been associated with poor differentiation, high TNM and BCLC staging, high AFP, intra-hepatic metastasis, vascular invasion, angiogenesis, high proliferation index and post-transplant recurrence; whereas inhibition of mTOR could suppress tumor growth and sensitize tumor cell to chemotherapy or other targeted therapies [53,54,56,57,[59][60][61][62]. In several preclinical studies, liver-specific TSC1 knockout mice showed constitutively elevated mTOR signaling and developed sporadic HCC [38,55,63,64].…”

Section: Discussionmentioning

confidence: 99%

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

Lashen¹

2017

JLRDT

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Background: In chronic hepatitis C (CHC) infection, liver disease progression results from viral persistence. Deregulation of target of rapamycin (TOR) signaling and autophagy is detected in viral infections and cancer. We studied the role of TOR and autophagy in the progression of CHC infection.Methods: 54 patients infected with HCV, [27 with CHC; 13 with cirrhosis and 14 with hepatocellular carcinoma (HCC)]; and 15 healthy subjects were included. Quantification of serum TOR was determined using enzyme linked immunosorbent assay. Tissue samples were immune-stained using TOR and autophagy protein 5 (Atg5) polyclonal antibodies. Expression of TOR and Atg5 was scored semi-quantitatively.Results: Expression and serum TOR were higher in HCC patients compared to patients without HCC (P< 0.05). Serum and expression of TOR were positively correlated to inflammation, fibrosis, steatosis and tumor characteristics (Alpha-fetoprotein, maximum diameter, tumor grade and CLIP stage) (P<0.05). Expression of Atg5 was inversely correlated with inflammation, fibrosis and tumor characteristics (P<0.05), Atg5 showed significant inverse correlation with serum and intra-hepatic expression of TOR (P<0.05). Serum TOR showed high sensitivity and specificity in discriminating infected patients with and without HCC at a cut-off value of 4.55 ng/ml [Area under ROC curve = 0.970]. Conclusion:Activation of TOR plays an important role in progression of HCV related liver disease possibly though autophagy suppression and they could be a potential therapeutic target. Serum TOR is a potential seromarker in discriminating HCV infected patients with and without HCC with high sensitivity and specificity.

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“…118 Temsirolimus: different phase I-II trials resulted in no favorable benefits of this combination. [119][120][121] …”

Section: Sorafenib Plus Mtor Inhibitorsmentioning

confidence: 99%

New modalities of treatment for hepatocellular carcinoma

Behnagh

Rezaei

Jahannia

et al. 2017

J. contemp. med. sci.

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Hepatocellular carcinoma (HCC) is the second most common cause of death from cancer worldwide. Managing HCC is difficult. However, there are many treatment options available such as liver transplantation, radiotherapy, different ablative techniques, surgery, trans-arterial chemoembolization (TACE) and systemic therapy. These treatments did not show the promising responses and the recurrence rate is still high. On the other hand, there are some new treatments such as immunotherapy, gene therapy, combination of different therapies, Chinese traditional therapies and new targeted therapies. The aim of this study is to review both the recent changes in the common therapies and newly developed therapies of HCC.

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Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates

Abstract: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Cited by 52 publications

References 38 publications

Management of recurrent hepatocellular carcinoma after liver transplant

Management of recurrent hepatocellular carcinoma after liver transplant

Target of Rapamycin (TOR) and Autophagy in Chronic Hepatitis C Virus Infection: Relation to Disease Activity

New modalities of treatment for hepatocellular carcinoma

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