Heterogeneity of liver cancer and personalized therapy

Li, Liang; Wang, Hongyang

doi:10.1016/j.canlet.2015.07.018

Cited by 247 publications

(154 citation statements)

References 110 publications

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“…HCC is characterized by extraordinary inter‐ and intra‐tumor molecular heterogeneity, which is probably responsible for the modest therapeutic response to molecular targeted agents. Future studies should aim at better characterizing and stratifying HCC patients into subgroups, according to their molecular profiles, in order to benefit from treatment with single molecular targeted agents or combinations of them under the heterogeneous conditions of HCC tumors …”

Section: Introductionmentioning

confidence: 99%

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

Augello

Emma

Cusimano

et al. 2018

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is a highly malignant tumor that responds very poorly to existing therapies, most probably due to its extraordinary inter‐ and intra‐tumor molecular heterogeneity. The modest therapeutic response to molecular targeted agents underlines the need for new therapeutic approaches for HCC. In our study, we took advantage of well‐characterized human HCC cell lines, differing in transcriptomic subtypes, DNA mutation and amplification alterations, reflecting the heterogeneity of primary HCCs, to provide a preclinical evaluation of the specific heat shock protein 90 (HSP90) inhibitor AUY922 (luminespib). Indeed, HSP90 is highly expressed in different tumor types, but its role in hepatocarcinogenesis remains unclear. Here, we analyzed HSP90 expression in primary human HCC tissues and evaluated the antitumor effects of AUY922 in vitro as well as in vivo. HSP90 expression was significantly higher in HCC tissues than in cirrhotic peritumoral liver tissues. AUY922 treatment reduced the cell proliferation and viability of HCC cells in a dose‐dependent manner, but did not do so for normal human primary hepatocytes. AUY922 treatment led to the upregulation of HSP70 and the simultaneous depletion of HSP90 client proteins. In addition, in a cell type‐dependent manner, treatment induced either both caspase‐dependent β‐catenin cleavage and the upregulation of p53, or Mcl‐1 expression, or NUPR1 expression, which contributed to the increased efficacy of, or resistance to, treatment. Finally, in vivo AUY922 inhibited tumor growth in a xenograft model. In conclusion, HSP90 is a promising therapeutic target in HCC, and AUY922 could be a drug candidate for its treatment.

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Section: Introductionmentioning

confidence: 99%

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

Augello

Emma

Cusimano

et al. 2018

Intl Journal of Cancer

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“…Finally, most trials were performed on viral hepatitis–induced HCC, which may not have the same histologic characteristics or pathogenesis as non-hepatitis–induced HCC. The biological heterogeneity of HCC makes the prognosis of tumor growth, survival of patients, and treatment outcomes difficult 100–102…”

Section: Introductionmentioning

confidence: 99%

Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway?

Ali

Laçin

Abdel-Wahab³

et al. 2017

OTT

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The epidemic of insulin resistance, obesity, and metabolic syndrome has led to the emergence of nonalcoholic steatohepatitis (NASH) as the most common cause of liver disease in the US. Patients with NASH are at an increased risk for hepatic disease-related morbidity and death, and chronic inflammation in NASH patients can lead to hepatocellular carcinoma (HCC). The prevalence of HCC is higher in males than in females, and genetic studies have identified androgen and androgen receptors (ARs) as partially responsible for the gender disparity in the development of liver disease and HCC. Although many factors are known to play important roles in the progression of inflammation in NASH patients, the role of androgen and AR in the progression of NASH to HCC has been understudied. This review summarizes the evidence for a potential role of androgen and the AR pathway in the development of NASH-related HCC and in the treatment of HCC. It has been proposed that AR plays a role in the progression of HCC: inhibitory roles in early stages of hepatocarcinogenesis and tumor-promoting roles in advanced stages. AR can be activated by several pathways, even in the absence of androgen. While AR has been explored as a potential therapeutic target in HCC, several clinical trials have failed to demonstrate a clinical benefit of antiandrogen drugs in HCC. This review discusses the potential reason for these observations and discuss the potential future trials design in this important setting.

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“…Especially, liver cancer is a highly inter- and intra-tumor heterogeneous disease [49] so that targeting multiple cancer-driving pathways has its advantage in cancer therapy. Notably, Pin1 promotes cancer development by turning on and off dozens of oncogenes and tumor suppressors, respectively [21].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the prolyl isomerase Pin1 enhances the ability of sorafenib to induce cell death and inhibit tumor growth in hepatocellular carcinoma

Zheng

Liao

et al. 2017

Oncotarget

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Hepatocellular carcinoma (HCC) is the sixth most common cancer, but is the second leading cause of cancer deaths, partially due to its heterogeneity and drug resistance. Sorafenib is the only medical treatment with a proven efficacy against advanced HCC, but its overall clinical efficacy is still modest. Therefore, a major challenge is how to improve its therapeutic efficacy. The unique prolyl isomerase Pin1 regulates numerous cancer-driving pathways. Notably, Pin1 is overexpressed in about 70% HBV-positive HCC patients and contributes to HCC tumorigenesis. However, the role of Pin1 in the efficacy of sorafenib against HCC is unknown. Here we found that sorafenib down-regulated Pin1 mRNA and protein expression, likely through inhibition of Pin1 transcription by the Rb/E2F pathway. Importantly, Pin1 knockdown potently enhanced the ability of sorafenib to induce cell death in HCC, which was further supported by the findings that Pin1 knockdown led to stabilization of Fbxw7 and destabilization of Mcl-1. Furthermore, all-trans retinoic acid (ATRA), a known anticancer drug that inhibits and ultimately induces degradation of active Pin1 in cancer cells, also potently sensitized HCC cells to sorafenib-induced cell death at least in part through a caspase-dependent manner. Moreover, ATRA also synergistically enhanced the ability of sorafenib to reduce Pin1 and inhibit tumor growth of HCC in mouse xenograft models. Collectively, these results not only demonstrate that Pin1 down-regulation is a key event underlying the anti-tumor effects of sorafenib, but also uncover that Pin1 inhibitors offer a novel approach to enhance the therapeutic efficacy of sorafenib against HCC.

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Heterogeneity of liver cancer and personalized therapy

Cited by 247 publications

References 110 publications

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway?

Inhibition of the prolyl isomerase Pin1 enhances the ability of sorafenib to induce cell death and inhibit tumor growth in hepatocellular carcinoma

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