Sorafenib: Where Do We Go from Here?

Siegel, Abby B.; Olsen, Sonja K.; Magun, Arthur M.; Brown, Robert S.

doi:10.1002/hep.23633

Cited by 101 publications

(104 citation statements)

References 78 publications

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“…One potential chemotherapeutic agent for this, sorafenib (Nexavar, BAY43-9006), is an oral multikinase inhibitor that blocks tumor cell proliferation and angiogenesis, and induces tumor cell apoptosis by inhibiting serine/threonine kinases (c-RAF and mutant and wild-type BRAF) as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 and 3 (VEGFR2 and VEGFR3), platelet-derived growth factor receptor β, FLT3 and c-KIT (5). Sorafenib is currently used in clinics to treat patients with advanced renal cell carcinoma, hepatocellular carcinoma and thyroid cancer (6)(7)(8)(9)(10). Moreover, preliminary data from a series of studies in which sorafenib was used in combination with a variety of anticancer agents for various solid tumors has been published (11).…”

Section: Introductionmentioning

confidence: 99%

The mechanisms responsible for the radiosensitizing effects of sorafenib on colon cancer cells

Kim

Jung

2014

Oncology Reports

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Abstract. Colorectal cancer is one of the most common malignancies in the world, and is generally treated more effectively by chemoradiotherapy rather than radiotherapy or chemotherapy alone. Targeted radiosensitizers are often used in order to enhance the radiosensitivity of tumor cells. The aim of the present study was to identify the mechanism of radiosensitization by sorafenib in colorectal cancer. Three human colorectal adenocarcinoma cell lines (HCT116, HT29 and SW480) were treated with sorafenib alone or radiation followed by sorafenib. In vitro tests were performed using colony forming assays, FACS analysis, immunohistochemistry, tumor cell motility assays, invasion assays and endothelial tube formation assays. Sorafenib enhanced the anti-proliferative effects of radiation, reducing colony formation, increasing G2/M arrest and enhancing radiation-induced apoptosis by reactive oxygen species. Sorafenib also inhibited the repair of radiation-induced DNA damage by blocking the activation of DNA-dependent protein kinase. Combination treatment significantly inhibited tumor cell migration, tumor cell invasion and vascular endothelial growth factor-mediated angiogenesis in vitro. Taken together, our results provide a scientific rationale for the use of sorafenib with radiotherapy in colon cancer and suggest a clinical utility for this approach.

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Section: Introductionmentioning

confidence: 99%

The mechanisms responsible for the radiosensitizing effects of sorafenib on colon cancer cells

Kim

Jung

2014

Oncology Reports

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“…Recent results of a phase 3 clinical trial showed that sorafenib, a multikinase inhibitor that blunts multiple signaling pathways, markedly improved survival in patients with advanced HCC tumors. 11,12 This pivotal study has stimulated scientific research on novel molecular therapies targeting specific signaling pathways to treat this malignancy. 6 A growing body of evidence suggests that persistent activation of STAT3 is oncogenic and is prevalent in a variety of human cancers, including liver cancer.…”

mentioning

confidence: 99%

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

Wang

Lafdil

Wang

et al. 2011

The American Journal of Pathology

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Aberrantly hyperactivated STAT3 has been found in human liver cancers as an oncogene; however, STAT3 has also been shown to exert hepatoprotective effects during liver injury. The balancing act that STAT3 plays between hepatoprotection and liver tumorigenesis remains poorly defined. In this study, the diethylnitrosamine (DEN)-induced liver tumor model and the chronic carbon tetrachloride (CCl 4 )-induced liver fibrosis model were both used to investigate the role of STAT3 in liver tumorigenesis. Hepatocyte-specific STAT3 knockout mice were resistant to liver tumorigenesis induced by a single DEN injection, whose tumorigenesis was associated with minimal chronic liver inflammation, injury, and fibrosis. In contrast, long-term CCl 4 treatment resulted in severe hepatic oxidative damage, inflammation, and fibrosis but rarely induced liver tumor formation in wild-type mice. Despite the oncogenic function of STAT3 in DEN-induced liver tumor, hepatocyte-specific STAT3 knockout mice were more susceptible to liver tumorigenesis after 16 weeks of CCl 4 injection, which was associated with higher levels of liver injury, inflammation, fibrosis, and oxidative DNA damage compared with wild-type mice. These findings suggest that the hepatoprotective feature of STAT3 prevents hepatic damage and fibrosis under the condition of persistent inflammatory stress, consequently suppressing injurydriven liver tumor initiation. Once liver tumor cells have developed, STAT3 likely acts as an oncogenic factor to promote tumor growth.

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“…6,7 Chemotherapy has showed limited efficacy and provides a survival advantage of only 2.3-2.8 mo in advanced HCC. 8,9 An attractive alternative to these current therapeutic options is immunotherapy, which is based on the sensitivity, specificity and memory of the immune system. However, immune regulation in the liver and tumor environment may contribute to tumor outgrowth and limit the efficacy of immunotherapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cellsex vivo

et al. 2015

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Sprengers (2015) GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cells ex vivo, OncoImmunology, 4:12, e1051297, DOI: 10.1080/2162402X.2015 Keywords: cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), hepatocellular carcinoma (HCC), liver metastases from colorectal cancer (LM-CRC), regulatory T cells (Treg)In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITRligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4 C Foxp3C Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.

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Sorafenib: Where Do We Go from Here?

Cited by 101 publications

References 78 publications

The mechanisms responsible for the radiosensitizing effects of sorafenib on colon cancer cells

The mechanisms responsible for the radiosensitizing effects of sorafenib on colon cancer cells

Hepatoprotective versus Oncogenic Functions of STAT3 in Liver Tumorigenesis

GITR engagement in combination with CTLA-4 blockade completely abrogates immunosuppression mediated by human liver tumor-derived regulatory T cellsex vivo

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