HERMIONE-2MAN · First in Man Novel Anticancer Therapeutic based on Dependence Receptors Concept

It is usually assumed that transmembrane receptors are inactive unless bound by their respective ligand. Against this dogma, the CLB proposed that some receptors may also be active in the absence of ligand and in this case trigger cell death. These receptors were called dependence receptors (DR) as their expression at the cell surface leads the cell to be dependent for its survival on ligand availability. The prototypic DRs are receptors DCC and UNC5H that bind their ligand netrin-1. The FP6 HERMIONE project (2006-2009) aimed to show DRs are negative regulators of tumor progression and to provide a setting in which DRs could be used in therapeutic perspective. The project was successful in these 2 aspects. Of interest, it was shown that in a large fraction of human cancers netrin-1 is autocrinally expressed to block DCC/UNC5H-induced apoptosis and that interference with netrin-1/receptors interaction is associated with tumor growth and metastasis inhibition in animal models of various cancer types. The results of HERMIONE and subsequent R&D performed by the HERMIONE-spin-off company Netris Pharma (NP) allowed the development of a promising anti-cancer drug candidate (anti-netrin mAb). Large pharmaceutical firms declared their interest to acquire this biologic after completion of human safety and possibly efficacy data. The challenge now is to bring rapidly and successfully this product to the patients. This requires maximum effort to develop the anti-netrin mAb production process, to perform preclinical regulatory toxicology and pharmacology, to evaluate the safety and gain some data on the efficacy of this biologic in human. The final objective of the project is a first-in-class first-in-man clinical trial. The HERMIONE-2MAN project will pave the way to an outstanding & innovative approach of cancer treatment, offering great clinical and market potential. The consortium gathers 1 academic partner (CLB), 2 SMEs (NP & Polymun) and a non-profit organization (EORTC).