C01: Optimization and evaluation of cmyc – directed liver cancer therapy

In patients suffering from advanced hepatocellular carcinoma (HCC), sorafenib is currently the only approved systemic treatment that results in a small survival benefit. Therefore, novel therapies are urgently needed. Deregulated c-myc expression frequently occurs in human liver cancers, however, a better understanding of the molecular downstream targets and their respective functional pathways is required to select the appropriate patients for c-myc-targeted therapies. The first aim of this project is therefore to dissect the role of c-myc in established liver cancers. We will use a recently developed DsiRNA against cmyc and inducible c-myc shRNAs in in vitro and in vivo HCC models to elucidate whether and how inhibition of c-myc impacts tumor growth. First, we will determine how c-myc inhibition affects tumor cell proliferation, cell death sensitivity, metabolism, and the tumor environment in HCC and to identify cell lines that are sensitive or resistant to c-myc inhibition. By using Microarray analysis, ribosome profiling, we aim to identify those downstream c-myc targets and functional pathways that determine sensitivity and resistance to c-myc based therapies in HCC. Due the profound genetic heterogeneity of HCC, most likely combination therapies are required for sufficient anti-tumor efficacy. Thus, the second part of our proposal focuses on optimizing c-myc directed therapies for the treatment of HCC. We will first combine rational targeted- and chemotherapies with c-myc inhibition. Moreover, we will perform a functional genomic shRNA screen to identify additional pathways to enhance c-myc-directed anti-cancer therapies. Together, the experimental program aims to unravel the functional role of c-myc in HCCs and to identify collaborating pathways to optimize c-myc targeted therapies.


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