Selective Inhibition of NOTCH by novel γ-Secretase Inhibitors in Tumours

Cancer remains one of the deadliest diseases and most deaths are due to treatment failure and metastasis.

Tumor resistance and patient outcome are strongly associated with tumor heterogeneity, which is promoted by the self-renewing and multipotent cancer stem cells (CSC) and by limitations in oxygen availability generating hypoxic areas within the tumor microenvironment.

The NOTCH signaling pathway is one CSC pathways frequently deregulated in human cancers but also essential in many normal tissues.

Given the widespread involvement in human cancers, many attempts have been made to target NOTCH (e.g. γ-secretase inhibitors, GSIs) and the hypoxic regions in the tumor (e.g. hypoxia-activated prodrugs, HAPs) in patients.

However, to date, GSIs and HAPs have not been successful in clinical studies due to limited anti-tumor responses and dose-limiting side-effects in healthy tissues.

As part of the ERC project DIRECT, I have leveraged our newfound knowledge on NOTCH signaling and hypoxia in tumors to develop two classes of novel NOTCH /g-secretase inhibitors (GSI) that enable tumor cell-specific inactivation of the NOTCH pathway (PSEN2-inhibitor) or by generating a dual-specificity NOTCH-inhibitor that is only released and active in hypoxic tumor regions (HyGSI) without affecting normal tissues.

This ERC PoC INGSIGHT will assess the technical and commercial feasibility of these two novel inhibitors of the NOTCH pathway with the potential to radically improve cancer therapy outcomes.

We will demonstrate the maximum tolerated dose in normal tissues and the therapeutic effects using five different tumor models.

We will solidify our IP position and we will conduct a market, competitor, and stakeholder analysis to ensure the selection of the most optimal business strategy.

As a result, we will gain technical and commercial Proof-of-Concept to determine the best route towards the commercialization of the PSEN2 inhibitor and/or HyGSI dual-specificity inhibitor.