LRIG1: an Endogenous Inhibitor for Pan-Receptor Tyrosine Kinase Targeting in Glioblastoma

Glioblastoma (GBM) is the most frequent and aggressive primary tumor of the human brain. Despite therapeutic strategies combining surgical resection, radiotherapy and chemotherapy, tumor relapses systematically occur and are associated with very bad prognosis. Current therapies should therefore be improved, based on well-defined specific molecular targets. The NorLux Neuro-Oncology lab has strong expertise in GBM research,with a special focus on anti-angiogenic treatment, tumor metabolism and genetic heterogeneity. Importantly, we developed clinically relevant animal models of GBM, which allow us to perform translational therapy studies for GBM. In this regard, we have shown the efficacy of an endogenous molecule (sLRIG1) with potent tumor suppressive effects against human GBM in vivo. sLRIG1 (soluble Leucine-rich Repeats and ImmunoGlobulin domains protein 1) was identified based on its inhibitory activity against the epidermal growth factor receptor (EGFR) and was later confirmed as a bonafide tumor suppressor protein. Since sLRIG1 was also found to be a negative regulator of other receptor tyrosine kinases (RTK), we proposed this molecule as a pan-RTK pathway inhibitor. We have shown that local delivery of sLRIG1 into the brain through encapsulated producer cells leads to a drastic reduction of tumor growth in mice. This was accompanied by a strong survival benefit of treated mice (Johansson et al. 2013). It is noteworthy that in this context, sLRIG1-dependent GBM inhibition was unrelated to EGFR level of expression or activation state, thus raising the question of the actual sLRIG1 signaling mechanism. In this project, we aim to precisely depict the molecular sequence of events that is elicited by sLRIG1 and that leads to tumor blockade. In particular, we will identify and validate interacting partners of sLRIG1 that are likely to play a key role in the inhibition of cancer progression. Furthermore, we want to identify the minimal active site of the protein that could be produced as an active therapeutic agent. This project will therefore generate a novel therapeutic molecule for the inhibition of growth factor signaling in GBM, and will pave the way for an unexplored therapeutic strategy against this dismal cancer.