andrea.loipetzberger
Cancer is a result of multiple genetic and epigenetic alterations that frequently lead to inappropriate activation of signaling pathways whose exquisite regulation is critical for normal cellular behavior and function.The cooperative interactions of distinct oncogenic signals have been shown to synergistically drive cancer development. The identification and in depth molecular analysis of such interactions is therefore an important step towards the development of rationale-based tumor therapiesinvolving combined targeting of interacting cancer pathways.
Our group has recently identified cooperative interaction of two clinically relevant druggable signaling pathways, the Hedgehog/GLI and EGFR pathway. Both pathways cooperate to induce oncogenic transformation by synergistic activation of cooperation response genes (CRG). Importantly, targeted inhibition of EGFR signaling is an efficient therapeutic strategy for the treatment of HH-driven cancers in preclinical models of non-melanoma skin cancer. Recent data of our group also suggests that cooperative interaction of HH/GLI and EGFR is critical for in vivo growth of human pancreatic cancer cells via promoting the tumor initiating capacity of putative cancer stem cells.
My doctoral thesis is building on these data and aims at the analysis of cooperative HH/GLI and EGFR interactions in tumor-initiating cells of pancreaticcancer, where both pathways play an etiologic role in tumorigenesis. In particular, I will focus on the functional characterization of previously identified HH/GLI-EGFR CRG in the determination of the malignant state and investigate the possible therapeutic benefit of rationale based combined treatments to target cooperative pathways in preclinical cancermodels.
Using genetic and pharmacologic approaches, the role of HH/GLI-EGFR CRG will be addressed in tumor initiating subpopulations of pancreatic cancer. Inhibition of functional CRG in combination with targeted disruption of HH/GLI or EGFR signaling will be evaluated in in vitro and in vivo tumorigenicity assays. Expression of CRG will be systematically analyzed in primary patient samples and correlated to the patients´ disease progression and survival. The study will contribute to a deeper understanding of the molecular cues regulating tumor initiating cancer cells in malignancies with high medical need and hopefully identify new opportunities for efficient cancer therapies based on combined inhibition of cooperative oncogenic signaling pathways.