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Novel targets and therapeutic strategies for the treatment of hepatocellular carcinoma (HCC)
Novel targets and therapeutic strategies for the treatment of hepatocellular carcinoma (HCC)
Liver cancer is a leading cause of cancer-related mortality worldwide and accounts for more than 800.000 deaths per year. Hepatocellular carcinoma (HCC) is a common cancer with high lethality, which is diagnosed most often at advanced stages when surgical or local treatment options are not possible. For the treatment of advanced HCC, sorafenib has been the only approved systemic treatment for nearly 10 years. Lately however, a number of additional compounds targeting tumour-specific signalling pathways, such as regorafenib, lenvatinib, and cabozantinib, and most recently, ramucirumab, provided positive results in phase-3 clinical trials. In addition, the approval of nivolumab as second-line treatment revealed the importance of the immune response in determining the development in HCC and set the stage for extensive clinical research with these agents. These new therapeutic options for HCC have significantly prolonged the life expectancy in patients with advanced-stage disease and collectively provided evidence that targeted therapy in different lines of treatment is a feasible strategy also for HCC. Nevertheless, a great individual variability in clinical benefits in response to these agents can be observed, and prognosis remains extremely poor in the majority of patients not responding to the treatments. By the two presented research projects, we aimed at assessing new therapeutic targets and possible therapeutic strategies for the treatment of HCC. In the first project, which was previously published in the form of an abstract, we explored the possibility of enhancing the therapeutic potential of sorafenib by its combination with the novel and clinically viable PI3K-Akt-Tor inhibitor copanlisib. To this regard, we found that copanlisib possesses potent anticancer activity as single agent and acts synergistically in combination with sorafenib in human HCC, hereby representing a rational potential therapeutic option for advanced HCC. In the second project, which was also presented and published as an abstract, we investigated the role of olfactomedin 4 (OLFM4), a glycoprotein predominantly expressed in bone marrow and gastrointestinal tract, in the pathogenesis of HCC. By performing immunohistochemical staining in human HCC tissues and functional in vitro assays of Huh7 and HepG2 cell lines, we provided the first report on a possible role of this molecule in determining the development of HCC by showing that increased expression of OLFM4 is a common event in the pathogenesis of this tumor with independent prognostic significance. Our preclinical results from these two studies, which are presented in the form of the two different manuscripts about to be submitted or published, warrant further investigation of PI3K-Akt-Tor signalling as a mechanism of cancer development and chemoresistance during HCC treatment, as well as of the role played by OLFM4 in determining invasion and metastasis in this tumor.
Hepatocellular carcinoma, sorafenib, copanlisib, OLFM4, prognosis
Ye, Liangtao
2019
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Ye, Liangtao (2019): Novel targets and therapeutic strategies for the treatment of hepatocellular carcinoma (HCC). Dissertation, LMU München: Faculty of Medicine
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Abstract

Liver cancer is a leading cause of cancer-related mortality worldwide and accounts for more than 800.000 deaths per year. Hepatocellular carcinoma (HCC) is a common cancer with high lethality, which is diagnosed most often at advanced stages when surgical or local treatment options are not possible. For the treatment of advanced HCC, sorafenib has been the only approved systemic treatment for nearly 10 years. Lately however, a number of additional compounds targeting tumour-specific signalling pathways, such as regorafenib, lenvatinib, and cabozantinib, and most recently, ramucirumab, provided positive results in phase-3 clinical trials. In addition, the approval of nivolumab as second-line treatment revealed the importance of the immune response in determining the development in HCC and set the stage for extensive clinical research with these agents. These new therapeutic options for HCC have significantly prolonged the life expectancy in patients with advanced-stage disease and collectively provided evidence that targeted therapy in different lines of treatment is a feasible strategy also for HCC. Nevertheless, a great individual variability in clinical benefits in response to these agents can be observed, and prognosis remains extremely poor in the majority of patients not responding to the treatments. By the two presented research projects, we aimed at assessing new therapeutic targets and possible therapeutic strategies for the treatment of HCC. In the first project, which was previously published in the form of an abstract, we explored the possibility of enhancing the therapeutic potential of sorafenib by its combination with the novel and clinically viable PI3K-Akt-Tor inhibitor copanlisib. To this regard, we found that copanlisib possesses potent anticancer activity as single agent and acts synergistically in combination with sorafenib in human HCC, hereby representing a rational potential therapeutic option for advanced HCC. In the second project, which was also presented and published as an abstract, we investigated the role of olfactomedin 4 (OLFM4), a glycoprotein predominantly expressed in bone marrow and gastrointestinal tract, in the pathogenesis of HCC. By performing immunohistochemical staining in human HCC tissues and functional in vitro assays of Huh7 and HepG2 cell lines, we provided the first report on a possible role of this molecule in determining the development of HCC by showing that increased expression of OLFM4 is a common event in the pathogenesis of this tumor with independent prognostic significance. Our preclinical results from these two studies, which are presented in the form of the two different manuscripts about to be submitted or published, warrant further investigation of PI3K-Akt-Tor signalling as a mechanism of cancer development and chemoresistance during HCC treatment, as well as of the role played by OLFM4 in determining invasion and metastasis in this tumor.