Dependence receptors (DRs) are transmembrane receptors which trigger apoptosis in the absence of their ligands. They have been shown to act as conditional tumor suppressors (Mazelin et al., Nature, 2004; Mehlen and Puisieux, Nat Rev. Cancer, 2006; Mehlen et al., Nat Rev. Cancer, 2011, Castets et al., Nature, 2012). It has been proposed that aggressive cancers may block the apoptosis induced by these receptors by up-regulating the ligand of these dependence receptors and that an appealing therapeutic strategy could be to block the ligand/receptor interaction. This has been demonstrated for the pair netrin-1/netrin-1 DRs (Mehlen et al., Sci. Signal. 2011; Mehlen et al., Nat Rev. Cancer, 2011). The preliminary results have confirmed the hypothesis that the increased expression of ligand could occur for other DRs and as such targeting ligand/receptor interaction may be proposed for other pairs of ligand/DR. The Sonic Hedgehog (SHH) signalling pathway is believed to play an important role in the development of several cancers, including prostate, colon, pancreas and brain cancers. Drugs targeting the downstream “canonical” signaling of SHH have been developed as exemplified by the Smoothened (Smo) inhibitor GDC-0449 (Metcalfe et al. Cancer Res., 2011). However, while these drugs appear to have some efficacy in a restricted number of cancers with mutations in the canonical pathway –Smo, Ptc, Gli-, they turned to be ineffective in other solid tumors where Hedgehog ligand is yet detected. The rational of this project is that SHH expression detected in a wide fraction of cancer is not a mechanism to activate the Smoothened-Gli canonical pathway but rather to block apoptosis induced by a recently discovered dependence receptor named CDO (Cell-adhesion molecule-related/Downregulated by Oncogenes, also named CDON). Recent unpublished but patented work achieved by the academic and the valorisation partners has (i) identified the receptor CDO as a SHH dependence receptor, (ii) shown that SHH expression in various cancer cells is a mechanism to block CDO pro-apoptotic activity and (iii) provided evidence that inhibiting SHH/CDO interaction is associated with tumor cell death in vitro and tumor growth inhibition in vivo independently of the classic Smoothened-Gli pathway. As a consequence, the main objective of the present proposal is to finalize the demonstration that pharmacological targeting of CDO to block CDO/SHH interaction is an efficient targeted therapy in cancers with high SHH expression, and to develop an anti-CDO drug candidate up to phase I clinical trial. The different tasks will then be: (i) To generate a human or humanized anti-CDO monoclonal antibody (mAb) blocking SHH/CDO interaction and to provide the animal proof-of concept that this antibody shows potent anti-tumor effect in animal models. (ii) To develop a manufacturing process, including fermentation and purification steps, for the production of the required amount of anti-CDO mAb required for regulatory pharmacology and toxicology studies. (iii) To complete a preclinical package including regulatory pharmacology and toxicology studies to determine the safety profile of the anti-CDO mAb and guide dosing in Phase I clinical trial. (iv) To identify the putative eligible responding population by analyzing SHH as well as CDO expression in human cancers. (v) To draft a clinical trial authorization application including key regulatory documents such as the investigator’s brochure and the study design of the phase I clinical trial to be conducted in patients with advanced cancers of various histology, selected for their expression level of SHH and CDO.

Over the last past years, the key roles of embryonic molecules/pathways in tumorigenesis have emerged and candidate drugs targeting these molecules/pathways have been developed. This has led to the clinical assessment developmental drugs/biologics and sometimes to clinical benefit for patients as targeting Sonic Hedgehog pathway in basocellular carcinoma. The current view is that the multistep program of tumorigenesis includes the reactivation of developmental processes like EMT, migration or apoptosis resistance. Several of these developmental proteins are axonal navigation cues. More specifically, the Mehlen group (P1) has previously demonstrated that the prototypical axonal guidance netrin-1 is up-regulated in a large fraction of human cancer as a mechanism supporting cancer cell survival. NETRIS Pharma (P2) has thus developed a monoclonal antibody (mAb) blocking netrin-1/receptors interaction which is now clinically assessed in a large phase II trial. Of interest preliminary data obtained by Partner 1 support the view that another netrin-1 related guidance cue named Draxin, is also up-regulated in a large set of cancers including Glioblastoma and, similarly to netrin-1, supports cancer cell survival. Together these preliminary data and the complimentary expertise of the academic and the private partners support the development of a therapeutic approach targeting Draxin in cancer. The DRAXCAN project will thus validate the Draxin target in cancer and preclinically develop a therapeutic anti-Draxin mAb. Target validation will include (i) the pan-cancer analysis of Draxin in human cancer using both public database and materials from in-house biobanks, (ii) analysis of Draxin silencing/interference in tumor cell models but also animal tumor models. The anti-Draxin mAb development will include (i) the generation of a series of blocking Draxin mAb, (ii) the selection of a candidate Draxin mAb showing tumor growth inhibition in mice models and (iii) its humanization.