NETRIS Innovative Concept
Biology teaches that cells survival is associated with external signals, which are then mediated by various transmembrane receptors and sensors. Such survival depends on various factors that include, among others, specific soluble trophic factors, cytokines, hormones, extracellular matrix interactions, cell-cell interactions, or electrical activity. Withdrawal of required stimulus leads to programmed cell death (or apoptosis). As a result, It was generally agreed that apoptosis induced by withdrawal of supporting factors was due to the loss of the associated positive survival signals. While such survival signals are clearly very important, data obtained over the past 20 years argue for a complementary form of signal transduction that actively induces cell death following stimulus withdrawal.
This “negative signal transduction” is mediated by specific “Dependence Receptors” (DRs), that induce apoptosis in the absence of the required stimulus (e.g., when unbound by a trophic ligand). As a result, the presence of various Dependence Receptors at the surface of the cells creates a state of dependence (or addiction) to their respective ligands.
To date, more than twenty of such receptors have been identified and this dual signal transduction (positive signaling upon ligand binding versus cell death upon ligand withdrawal) has been shown to play major roles during embryonic development and regulation of tumoral progression.
Focus on Oncology
Because of their intrinsic duality, Dependence Receptors are described as negative regulators of tumor progression, while their respective ligands have pro-tumoral role. Hence, in a large fraction of cancers, the cancer cells and/or the tumoral microenvironment are causing a self-production (i.e., autocrine or paracrine production) of the dependence receptor ligand. This ligand self-production has been shown to be a selective tumoral advantage both for cancer cell survival but also for potentiating cancer cell plasticity and thus escape most of the current approved therapies.
Therapeutic strategy : NETRIS Pharma focuses its activities on the therapeutic potential of interfering with the ligand-dependence receptor interaction, with the aim to both induce cancer cell death and alleviate resistance to chemotherapies, targeted therapies and immune-checkpoint inhibitors
Most anti-cancer therapies currently available are targeting highly proliferative cancer cells. However, the past decade has shown that resistance to these therapies is intrinsically linked to the ability of a subset of cancer cells to escape these treatments through phenotypic changes. The therapeutic strategy of NETRIS Pharma is to develop novel drugs inhibiting cancer plasticity, that should thus not only control tumoral progression but also potentiate long term efficacy of chemotherapies, targeted therapies and immunotherapies. NETRIS Pharma’s strategy is to block the interaction between the ligand and its Dependence Receptor to restore cell death and inhibit phenotypic plasticity. Such targeted approach includes the development of biomarker strategies to select patients. The relevance of this strategy has been validated through an extensive set of preclinical experiments and was further strengthened by the positive outcome of the Phase 1 clinical trial assessing the NETRIS Pharma lead asset NP137 in patients with advanced solid tumors.
restoration of the pro-apoptotic mechanism