FWO-SB-beurs: Innovation through Combination: Identification of a novel combination therapy for improved treatment of EGFR (FWOSB5)

Lung cancer is the leading cause of cancer related deaths worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype of the disease. Frequently occurring oncogenic Epidermal Growth Factor Receptor (EGFR) gene mutations in NSCLC confer sensitivity towards EGFR tyrosine kinase inhibitors (TKIs). Despite encouraging clinical efficacy of these EGFR TKIs, the majority of patients relapse within the first year of therapy. Many studies have identified emerging resistance mechanisms responsible for therapeutic resistance, however it remains largely unclear which mechanisms reduce the initial therapeutic effects. The development of EGFR TKI-based combination therapy that potentiates initial therapy remains a major challenge in order to achieve improved treated patients’ outcomes. In this project, we will focus on the improvement of the (initial) targeted therapy of EGFR mutant NSCLC. The endpoint of this study will be the identification and preclinical validation of a combination therapy targeting both EGFR and a novel co-target (or pathway) responsible for the reduced therapeutic effects of EGFR TKIs. We have performed a high throughput RNAi screening aimed to identify candidate co-targets causing EGFR insensitivity in human EGFR mutant NSCLC. Based on this approach, we have identified a total of 37 components of the ubiquitin or kinase pathways. This IWT project is based on the preliminary data of the RNAi screen and is composed of: Aim1: Validation of the RNAi screen results & lead target selection Aim 2: Characterization of molecular and cellular mechanisms Aim 3: In vivo validation of (a) potential combination therap(y)ies The RNAi screen (that included 4609 targets) identified proteins that, when silenced, increased the effect of afatinib (an EGFR TKI used in clinic). We will first validate the 37 candidates and a selection of the top co-targets will be further used in the subsequent parts of the study. Possible combination therapies will be evaluated in various cell lines, with different EGFR TKIs, siRNAs and/or drugs inhibiting the co-targets. The second aim will identify molecular mechanism(s) of action instigating the inhibition of the co-target(s) and enhancing EGFR targeted therapy. We will evaluate effects on cell cycle, apoptosis, and specifically analyze crosstalk mechanisms between the co-target and EGFR signaling. Understanding the mechanism(s) of action may also reveal additional druggable co-targets that will be also evaluated in combination with EGFR TKIs. At last, we will validate the most promising combination therapies in vivo using xenograft models harboring NSCLC cell lines or patient derived tumor tissues, and RNAi technology or drugs against the co-targets, in combination with the optimum EGFR TKI. For this IWT project we have set up a fruitful collaboration with the Sanford-Burnham-Prebys Medical Discovery Institute (La Jolla, California, USA). This collaboration ensured a cutting-edge RNAi screen. Additionally, we are also collaborating with the PACS laboratory headed by Prof. Gutierrez (VUB, campus Etterbeek), who is a co-promoter and expert in the ubiquitin field. Finally, an agreement has been reached with Boehring-Ingelheim in order to guide us to translate our findings into a medical and economically exploitable innovation.

Keywords:lung cancer

Disciplines:Cancer therapy

Project type:Collaboration project