1.) Molecular pathogenesis of liver cancer
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the predominant primary hepatic tumors in the adult, whereas hepatoblastoma (HBL) is the main liver pediatric neoplasia. Regardless of the histologic type, liver tumors are highly aggressive malignancies with very limited treatment options when they are surgically unresectable. We are investigating the oncogenic role of various signaling pathways as well as their functional interplay in the three liver tumor types in terms of tumor development and progression, using a comprehensive approach that consists of preclinical mouse models generated via the hydrodynamic gene delivery method, tumor derived cell lines, and human specimens. Major signaling cascades currently under investigation from our group are the Notch, Hippo/Yap, Wnt/Beta-catenin, and PI3K/AKT/mTOR signaling pathways and their crosstalk.
2.) Tumor metabolism
Mounting evidence indicates that metabolism reprogramming is one of the hallmarks of cancer. In this regard, we are involved mainly in the investigation of aberrant lipogenesis in liver tumors. We are intensively investigating the molecular mechanism that render cancer cells (not limited to the liver) sensitive or resistant to fatty acid synthase (FASN; the main enzyme involved in fatty acid synthesis) depletion and the cellular/molecular consequences of lipogenesis deregulation. Currently, we are also investigating the importance of the SREBP2 (sterol regulatory element binding protein 2)/mevalonate pathway in the oncogenic process. Our recent data indicate that activation of the SREBP2/mevalonate pathway takes place as a compensatory mechanism triggered by FASN inhibition. Thus, we are assessing the relevance of fatty acid synthesis/mevalonate pathway dual inhibition as an efficient strategy for the treatment of hepatocellular carcinoma.
3.) Innovative targeted-therapies for cancer
Therapies being able to target specific molecular alterations in cancer cells while sparing the normal cells are an unmet need in oncology, especially for treating tumors at an advanced stage. This is particularly relevant for cancer entities such as HCC and cholangiocarcinoma, which only minimally respond to the available chemotherapeutic treatments. Using rodent and cell line models, we are addressing the potency of novel targeted therapies directed against hepatocellular carcinoma, cholangiocarcinomas, hepatoblastomas, and other solid tumors (colorectal, pancreatic, etc.). In particular, we are developing and analyzing therapies in which simultaneous inhibition of the PI3K/AKT/mTOR and Ras/MAPK signaling cascades is implemented. Furthermore, we are investigating and targeting with experimental therapeutics the mechanisms of resistance to conventional chemotherapies that are present in cancer cells.