ANTINETREX

In the cancer field, targeted therapies represent the main focus of large pharmaceutical companies and are still considered as the Holy Grail for most clinical oncologists. However, so far the gain in term of overall survival is very limited and one of the key limitation is the difficulty to predict a response. The current paradigm is that a targeted treatment should be given if the target is detected, which is nearly tautological. However, the presence (or the alteration) of the target is insufficient per se to predict the response to a specific drug. This issue is of tremendous importance during the course of early clinical development where only a limited number of patients are tested and where the apparent absence of benefit after patient stratification solely based on the expression/alteration of the target is sufficient to stop any further development. The group of P. Juin (Nantes Angers Cancer Center, Team 8 (NACC)) and its spin-off Oncotherex have developed a procedure where they can, from a tumor biopsy or a surgical specimen, culture for two-three days tumor tissue sections ex vivo. During this lapse, the effects of candidate drugs on the biology of these sections (proliferation, apoptosis) can be analyzed. This, if applied to early clinical protocol, could be a very efficient help to identify patients who may benefit from the treatment, in case of good correlation between ex vivo response on tumor tissue sections and clinical response, and could enhance the identification of biomarkers predictive of response. Furthermore, the analysis of these tumor tissue sections will provide new clues to better understand the underlying mechanisms of action of the drug on the whole tumor, as tumor cells are interacting with their microenvironment. Netris Pharma, a spin-off of P.Mehlen and the Centre Leon Bérard (CLB; P. Mehlen) are preparing an early clinical trial on a first-in-class first-in-man monoclonal antibody raised against a ligand (netrin-1) which blocks tumor cell death constitutively induced by dependence receptor (DCC, Unc5s). Of interest data obtained in vitro and in various animal models support the view that the developed antibody is showing a much better efficiency in complex settings where tumor cells are accompanied by the stroma than in classic cell culture that poorly represents the human pathology. These tumor tissue sections including real human tumor settings with tumors cells and stroma being conserved may thus represent a very interesting tool to better understand the effect of the antibody and predict putative patient response. The present project shall thus aim at the development of a proof-of-concept study where apoptosis induced by the netrin-1 antibody in tumor tissue sections obtained from breast cancer and ovarian cancer patients will be evaluated. From promising preliminary data showing the netrin-1 antibody is able to show clear tumor cell death in the small set of tumor tissue sections assessed, the project is willing to reach the following main objectives: (i) Evaluate the activity of the innovative therapy against netrin-1, using the antibody as single agent and in combination with chemotherapies and targeted therapies, in the new procedure of patient derived tissue tumor sections (ii) Determine predictive markers of response to the anti-netrin-1 antibody and possibly obtain new hints on the netrin-1 dependence receptor pathway and resistance to this pathway. (iii) Develop a predictive clinical test of the efficacy of the new therapy to define the eligible population.