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Clinical Research Group KFO119

Hepatocellular carcinoma – a challenge for translational research

Hepatocellular carcinoma (HCC) constitutes the fifth most frequent cancer worldwide and due to a lack of treatment options, HCC represents the third most lethal cancer worldwide. The incidence of HCC is continuously rising in Europe and Northern America, which can be explained by spreading of Hepatitis C virus infections. Although human hepatocarcinogenesis serves a model for virus induced tumor development, growth of human HCC is not dependent on single viral oncogenes and the majority of the virus associated HCC do not even express any viral gene, indicating development by a hit-and-run mechanism. Thus pharmacological or immunological targeting of viral genes appears to be not a promising strategy for HCC therapy. Currently targeted therapy of HCC angiogenesis (via VEGF-inhibitors) is the most promising strategy for systemic treatment of patients with HCC and most oncologists believe that personalized oncology is the future of HCC treatment. Personalized oncology includes the individual analysis of alterations in a given tumor at the epigenetic, transcriptional and protein level for the subsequent specific treatment of the altered pathways by molecular drugs. However, successful personalized targeted therapy has to inhibit pathways which are necessary for tumor growth, even at late stages of carcinogenesis. Thus one of the challenges of personalized oncology is the discrimination of driver versus bystander alterations. The p16/Rb-, p53-, and IGF2R-checkpoints as well as oncogenic alterations of telomerase, c-myc, Wnt/ß-catenin-, PI3K/Akt-, hedgehog-, and c-met/HGF-are most frequently involved in human hepatocarinogenesis. Although little is known about the essential oncogenic networks in HCC, combination of different drugs that are directed against these pathways is the most promising strategy for clinical trials in the near future. However, to achieve a real breakthrough in targeted therapy of HCC a detailed knowledge of the molecular pathogenesis with identification of key alterations is necessary. With the help from suitable HCC models, human HCC tissue, comparative oncogenomis and target evaluation in animal models we want identify in the KFO-119 research projects the key targets in different oncogenic networks, which would enable us to establish an effective individualized targeted HCC therapy in the future.

The clinical research group KFO-119

The Medical School Hannover is internationally most renowned for transplant medicine and related immunological fields, disorders of the immune system and infectious diseases (particularly of the liver) as well as paediatric and adult oncology. In view of the great expertise regarding liver tumours, Medical School Hannover was provided in January 2004 with a grant from the Deutsche Forschungsgemeinschaft (German Research Association) to set up a clinical research group (KFO 119) with topic ”Hepatocellular carcinoma: molecular bases and consecutive experimental therapeutic approaches”. The Clinical Research Group KFO-119 is now in its second period. The general aim of the KFO-119 is to gain a profound understanding of the molecular and immunologic basis of murine and human hepatocarcinogenesis beginning with the initiation in chronic liver disease to its progression into advanced cancer and metastatic disease. The long term strategy of KFO-119 includes the analysis of basic molecular and immunological mechanisms involved in HCC development and investigating new concepts for the treatment of HCC. Its closely interacting research projects will first translate the basic results (yellow/orange) into preclinical animal studies (light blue) and finally into clinical phase I/II studies (dark blue):

Current projects of the KFO-119 clinical research group

Project 1 Lehmann / Kreipe

The research by Ulrich Lehmann and Hans Kreipe has focused on the role of epigenetic changes in HCC development and progression. Over the last years, they have shown that changes in methylation pattern are early events in tumorigenesis by characterizing tumor type-specific methylation patterns. In addition they showed that human liver adenomas have significantly different methylation patterns compared to human hepatocellular carcinomas and that the methylation of genes in human liver is age dependent. The current project focuses on gene methylation patterns as diagnostic tools for assessment of HCC development and prognosis. In addition Ulrich Lehmann and Hans Kreipe want to characterize microRNA methylation patterns and expression profiles in hepatocarcinogenesis and they want to evaluate how altered microRNA epigenetics reflect the etiology and impact the risk of transformation in pre-cancerous conditions.

Project 2 Wilkens / Schlegelberger

The group of Brigitte Schlegelberger and Ludwig Wilkens has an international reputation in the characterization of differentially expressed genes in HCC and tumor-associated chromosomal alterations. They showed that human liver adenomas have significantly different gene expression patterns compared to human hepatocellular carcinomas. In addition they have previously shown that chromosomal instability is associated with de-differentiation of HCC and that this process is paralleled by histone deacetylase overexpression and the loss of histone acetylation, a common event in liver carcinogenesis. Currently they want to test the hypothesis that the resulting chromatin remodeling alters the expression of specific microRNAs and ultimately leads to increased proliferation and genetic instability. For these investigations they want to apply specific targeting of histone deacetylation and global expression analyses in cellular model systems and subsequently they want to compare the results of the cellular model systems with patterns in human HCCs.

Project 3 Rudolph / Schlegelberger

Previously Lenhard Rudolph and Brigitte Schlegelberger showed the impact of telomere shortening and p53 deletion on hepatocarcinogenesis in a mouse model. In these experiments they revealed that p53-independent checkpoints inhibit the progress of hepatocarcinogenesis after telomere disruption and chromosomal instability. Furthermore they demonstrated that activation of telomerase prevents the occurrence of severe chromosomal instability in the preneoplastic cells and thereby accelerates the progression of hepatocarcinogenesis. In the current project Lenhard Rudolph and Brigitte Schlegelberger want to identify and characterize the p53-independent checkpoints in the telomerase/p53-HCC mouse model.

Project 4 Malek

The Malek group concentrates on basic mechanisms of cell cycle regulation and the analysis of dysregulation in proteolytic degradation of cyclin E and p27. In a p27-directed drug-screening approach they recently found the new proteasome-inhibitor Argyrin, which will be soon investigated in a clinical phase I study at the MHH. In addition Malek and his group investigated the contribution of E3-ubiquitin ligase in the biology of HCC stem cell development. Ablation of a specific subunit of E3-ubiquitin ligase results in the persistence and massive expansion of hepatic progenitor cells. Loss the E3-ligase subunit and p53 leads to the formation of primary hepatocellular carcinomas in double knockout animals, providing a model in which E3-ligase is necessary to prevent the formation of progenitor cells with a great potential for transformation into HCC stem cells.

Project 5 Strassburg/Buer

Project Strassburg / Buer is the consequent continuation of the group’s longstanding and successful work on genetic variability in drug metabolism and detoxification and its predisposing role for hepatocellular carcinoma. The group was the first to demonstrate this phenomenon for the UDP-glucuronosyltransferase family of detoxifying enzymes. UGT variants influence the metabolic effects of xenobiotic exposure and therefore have been linked to cancer risk. Detailed knowledge of the organization, function, and pharmacogenetics of the human UGT genes is likely to significantly contribute to the improvement of drug safety and efficacy as well as to the provision of steps toward the goal of individualized drug therapy and HCC disease risk prediction. The current aim of the project is the functional in vivo characterization of the UGT-modulated hepatocarcinogenesis using a humanized transgenic UGT-SNP/C57BL/6 transgenic mouse.

Project 6 Greten

The Greten group have demonstrated mechanisms by which HCC cells evade immune surveillance, such as increased numbers of Tregs and defects in antigen presentation. Tim Greten and Firouzeh Korangy identified a new myeloid suppressor cell (CD14(+) HLA-DR(-/low)) in human HCC. CD14(+) HLA-DR(-/low) cells were unable to stimulate an allogeneic T-cell response, suppressed autologous T-cell proliferation and NK cells and had high arginase activity, a hallmark characteristic of MDSC. Most important, CD14(+)HLA-DR(-/low) cells from HCC patients induced a CD4(+)CD25(+)Foxp3(+) regulatory T-cell population when cocultured with autologous T cells. Consequently the Greten group propose a new mechanism by which MDSC exert their immunosuppressive function, through the induction of CD4(+)CD25(+)Foxp3(+) regulatory T cells in cocultured CD4(+) T cells. They have carried their knowledge into clinical application by establishing a clinical phase I/II study in patients with HCC.

Project 7 Kubicka / Manns

Virotherapy elicits an antitumoral immune response by cross-presentation of tumor antigens. Stefan Kubicka and Florian Kühnel have developed a highly innovative viro-therapeutic approach that combines the therapeutic efficiency with improved tumor cell specificity by exploiting tumor cell-specific molecular alterations, especially in the telomerase- and p53- pathway. They recently showed that virotherapy is capable of overcoming tumor-specific immune-tolerance mechanisms and demonstrated the improvement of virotherapy-induced antitumor immune responses by the recruitment and expansion of dendritic cells (DC) at the site of oncolytic viral infection. The aim of the current project is the identification of cytokine/chemokine-combinations for the optimized recruitment and expansion of DC. In addition, they want to investigate the molecular mechanisms involved in virotherapy-induced cell death that support the antitumoral immune responses due to improved uptake and cross-presentation of tumor antigens by DC.

Personal changes of the KFO 119 during the last 3 years
Three excellent project leaders (Lenhard Rudolph, Jan Buer and Ludwig Wilkens) were promoted to a full professorship appointment at the University of Ulm (Rudolph), University of Essen (Buer) and University of Bern (Wilkens) , while another young investigator (Lars Zender) was recruited back from the U.S.A. after completing a three year postdoctoral fellowship (supported by the Emmy Noether program).