Hepatocellular carcinoma (HCC) is currently one of the most common and fastest growing tumors contributing significantly to morbidity and mortality in Europe and the US. Current medical therapies have recently improved but continue to have only moderate effectiveness with median survival rates of significantly less than two years for advanced HCC. To date, the most successful therapies target only the tumor microenvironment, and there are no highly effective therapies that directly target tumor cells. Furthermore, it is important to consider the extremely distinct heterogeneity of the tumor in order to ensure therapeutic efficacy. In this proposal, I seek to develop novel therapeutic targets in tumor cells. Focusing on tumor cell intrinsic MR. I hypothesize that (a) tumor cell intrinsic gene regulatory networks, controlled by transcriptional master regulators (MR) have aberrant activity in tumor cells and that these MR are shared by patients with different mutational profiles; (b) that MR provide novel and much needed therapeutic targets, and that targeting tumor cell MR may account for the genetic heterogeneity of HCC; and (c) that targeting tumor cell-intrinsic MR could synergize with TME-directed immunotherapies and In three specific aims, I seek to establish relevant HCC MR, determine their function in vivo and in human cell lines, and determine synergies with TME-directed therapies.
DFG Programme
WBP Fellowship
International Connection
USA
