Pancreatic cancer : Promising drug candidate identified
Marseille, May 15, 2019. Scientists from the Cancer Research Center of Marseille (CRCM) have identified a chemical compound that presents effective and specific antitumor activity against pancreatic cancer in an experimental model, in collaboration with a team from the Interdisciplinary Center for Nanosciences in Marseille, a team of Chinese chemists and an Italian bioinformatics team. This promising drug candidate will soon be the subject of a clinical trial.
All cells in the body have "warning" systems that they use to defend themselves from attacks or situations of suffering, interpreted by the cells as stresses to which they respond to adapt and survive. The team of Dr. Juan Iovanna, Research Director at the Cancer Research Center of Marseilles (CRCM) has studied and identified most of these mechanisms of stress response, and identified the genes involved. Among these genes, NUPR1 is particularly original because it is systematically activated in cancer cells. Why is NUPR1 activated in pancreatic cancer and not in healthy cells? Because the tumor develops in a disorganized manner in a very unfavorable, hostile environment, with little oxygen and nutrients. In this context, many cells die because they do not adapt. But the cells that manage to activate the warning systems effectively survive and are particularly resistant. This is probably one of the reasons why pancreatic cancer is so aggressive. Persistent activation of these defense systems disrupts the functions of cancer cells that become completely dependent on the activity of these stress response genes. Thus, these genes are particularly promising therapeutic targets, but so far poorly exploited.
Juan Iovanna's team focused on studying the NUPR1 stress gene and implemented several genetic approaches to inactivate it in cancer cells, demonstrating that pancreatic tumors stop growing as soon as this gene is inactivated. After this work was published, other laboratories around the world have shown that the same effect can be obtained on tumors of the liver, brain, bile ducts, and colon among others, indicating that this phenomenon is not limited to pancreatic cancer. These results justify the search for drugs capable of inhibiting the activity of the NUPR1 gene chemically.
Juan Iovanna's team then began researching for chemical inhibitors of NUPR1 from the thousands of drugs already on the market, and used for the treatment of various diseases. They were able to identify Trifluoperazine, an anti-psychotic drug used until recently as a good inhibitor of NUPR1 activity. Juan Iovanna's team showed that the drug has anti-tumor effects but, at the required doses, shows undesirable effects on the central nervous system, making it unusable as is.
Nevertheless, the structure of Trifluoperazine served as a basis for synthesizing new compounds which are more effective and have fewer side effects. Molecular modeling of the complex that Trifluoperazine forms with NUPR1 has allowed them to predict that several dozen compounds may be more active and less deleterious to the central nervous system. Among these new compounds, the ZZW-115 molecule has an anti-tumor effect more than ten times greater than that of Trifluoperazine on pancreatic cancer by causing the complete disappearance of tumors in experimental models, and especially without the undesirable effects. ZZW-115 appears to be an excellent candidate for the treatment of pancreatic cancer. These results have just been published in the Journal of Clinical Investigations, and the anti-tumor activity of ZZW-115 is now protected by a patent filed by Inserm Transfert. The exploitation of these results will be entrusted to a new biotechnology company (PanCa Therapeutics), which will be established shortly in the Sud Provence Alpes-Côte d'Azur region, and whose specific objective is to bring this drug into clinical applications. The next phases are the toxicity and pharmacokinetics studies, before moving on to the clinical trials that should be carried out in Institut Paoli-Calmettes.
Reference Ligand-based design of a potent inhibitor of NUPR1 exerting anticancer activity via necroptosis
SantofimiaCatano P, Xia Y, Lan W, Zhou Z, Huang C, Peng L, Soubeyran P, Velazquez-Campoy A, Abian O, Rizzuti B, Neira JL, Iovanna JL.
Journal of Clinical Investigations 2019, doi.org/10.1172/JCI127223
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About CRCM Created in 2008, Marseille Cancer Research Center (CRCM) includes the four major stakeholders in research in PACA : Inserm, CNRS, Aix-Marseille University and Paoli-Calmettes Institute. With 400 staff members divided into 19 teams, the CRCM implements innovative research programs in cancer, the most fundamental aspects of clinical research in humans.
The priority scientific and medical activities are, on the one hand, the decoding of molecular bases of oncogenesis and tumor dissemination, and on the other hand, the discovery and implementation of therapeutic innovations in the treament of breast and pancreatic cancers and hematologic malignancies. The CRCM is one of th founding members of the cluster Marseille Immunopole.
Further information : www.crcm.marseille.inserm.fr
Contacts press :
Dr Juan IOVANNA - +33(0)4 86 97 88 03 Juan.iovanna(at)inserm(dot)fr
Elisabeth BELARBI +33(4) 91 22 37 48 belarbie(at)ipc.unicancer(dot)fr