RPIB - Recherches Partenariales et Innovation Biomédicale

Toward an alternative anticancer therapeutic strategy targeting the Hedgehog pathway using the dependence receptor paradigm – DepR-SHH

Submission summary

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 Recent unpublished but patented work achieved by the academic and the valorisation partners has (i) identified the receptor CDO as a SHH dependence receptor, (ii) shown that SHH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.

Project coordination

Patrick MEHLEN (Centre de Recherche en Cancérologie de Lyon, Equipe Apoptose, Cancer et Développement, UMR Inserm 1052 - CNRS 5286)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CLB Centre Léon Bérard
CRCL Centre de Recherche en Cancérologie de Lyon, Equipe Apoptose, Cancer et Développement, UMR Inserm 1052 - CNRS 5286
NP Netris Pharma

Help of the ANR 816,999 euros
Beginning and duration of the scientific project: December 2013 - 30 Months

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