Targeting-enhanced activation of Galectin-1 for cancer therapy

Contemporary anti-cancer strategies eliminate cancer cells by activating classical apoptosis signaling routes. Unfortunately, cancer cells can escape from therapy due to intrinsic or acquired resistance. Moreover, these therapies often display dose-limiting toxicity towards normal cells/tissues. The proposed project aims to develop a novel therapeutic strategy to activate non-classical apoptosis signaling in cancer cells in a spatiotemporally-restricted manner. Hereto, I exploit the promising therapeutic features of Galectin-1 (Gal-1). Monomeric Gal-1 is largely inactive. In contrast, homodimeric Gal-1 potently activates non-classical apoptosis signaling in various cancer cell types. An important clinical limitation is the fact that non-covalent Gal-1 dimers are only formed at extremely high concentrations. This project aims to design and engineer novel recombinant Gal-1 variants with enhanced therapeutic value. Hereto, I will genetically fuse Gal-1 monomers to a tumor-selective antibody fragment (scFv), yielding scFv:Gal-1 fusion proteins. The proposed mode of action is that scFv-mediated binding of scFv:Gal-1 leads to specific accretion at the cell surface of targeted tumor cells. Consequently, the local concentration is increased, yielding active scFv:Gal-1 dimers. Thus, scFv:Gal-1 activity will be spatiotemporally-restricted to targeted tumor cells. The project will integrate state-of-the-art knowledge from various disciplines to engineer and evaluate the therapeutic potential of scFv:Gal-1 for cancer therapy.