NUPR1, an intrinsically disordered nuclear protein (IDP), plays a crucial role in pancreatic cancer (PDAC) and other types of cancer. NUPR1 plays a crucial role in regulating tumor growth, and its genetic inactivation results in a complete halt to tumor development. Due to the unique structural characteristics of intrinsically disordered proteins, the development of specific inhibitors for NUPR1 remains a major challenge.

Our team is tackling this problem using innovative, multidisciplinary approaches. Our research has led to the discovery of ZZW-115, a potent anticancer compound tested in vitro and in vivo. Using ZZW-115, we observed dose-dependent tumor regression in xenograft mice, with no apparent side effects. Our cellular analyses revealed that ZZW-115 induced necroptosis, apoptosis and ferroptosis in response to mitochondrial destabilization, highlighting its therapeutic potential.

Our most recent results show that ZZW-115 inhibits the formation of NUPR1-dependent stress granules, thereby slowing the progression of pancreatic intraepithelial neoplasia (PanINs) in mice carrying the oncogenic KrasG12D mutation. This inhibition led to cell death, caspase 3 activation, DNA fragmentation and the formation of apoptotic bodies after four weeks' treatment.

Our team continues to explore these mechanisms to offer new therapeutic perspectives in the fight against NUPR1-dependent cancers.

Ongoing research is focusing on ZZW-115's mechanism of action, NUPR1's molecular partners, its synergy with DNA-damaging agents and regulatory preclinical studies. The ZZW-115 compound has been granted patent protection, and a start-up company (PanCa Therapeutics) has been set up to take it into clinical trials.

We have validated the efficacy of these signatures in several retrospective studies, and our current work focuses on their clinical validation in prospective cohorts. The Pancreas-View algorithm, protected by a patent, has given rise to a start-up company, Predicting Med, created to ensure its industrial development. This initiative aims to integrate this innovative tool into routine clinical practice, in order to improve the management of pancreatic cancers.

By adopting this multidisciplinary approach, our aim is to develop innovative therapeutic strategies capable of overcoming tumor resistance, thereby improving the efficacy of chemotherapies and opening up new perspectives for the management of PDAC.

Our goal is to identify these pancreatic cancer-associated alterations for use as markers of chemoresistance and as novel molecular targets for re-sensitization. Thus, restoring normal TPM of some of these targets has the potential to restore the sensitivity of pancreatic cancer cells to conventional therapies, thereby increasing their efficacy and hence patient survival.

Our project therefore aims to characterize the molecular and clinical impact of these glycosyltransferases and the aberrant glycans they produce. The aim is to determine their potential as histological glyco-biomarkers predictive of response to treatment. We are also exploring their role in the molecular mechanisms involved both in tumor progression and in modulating sensitivity or resistance to chemotherapies.