A new pharmacological approach to reduce the progression of pancreatic cancer

Research published in the journal Gastroenterology, involving researchers from the Departments of Experimental Medicine and Chemistry and Technology of Drugs at Sapienza, has identified a potential adjuvant pharmacological strategy to conventional pancreatic cancer therapy, based on the activation of a specific enzyme involved in tumour metabolism

To date, pancreatic cancer is a virtually intractable tumour, making it the seventh leading cause of cancer death worldwide. The reason for this is that this tumour develops in a particularly hostile microenvironment, with reduced oxygen tension and limited nutrient supply, which leads pancreatic cancer cells to reprogram their metabolism, thereby gaining proliferative advantages over normal cells.

Recently, a class of seven enzymes, called sirtuins, has been shown to be involved in tumour progression. They can modify other proteins due to their role in regulating metabolism, the tumour microenvironment and the genomic stability of cancer cells. Among these, sirtuin 5 (SIRT5), located in the mitochondria and cytosol, has been linked both to the regulation of metabolism in general and, in particular, to that of the amino acid glutamine in several tumour types.

That is the background to a new international study published in the journal Gastroenterology, which involved a team of researchers from the Departments of Experimental Medicine and Chemistry and Technologies of Drugs at Sapienza University, together with the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska and other international research centres. The work aimed to define the function of SIRT5 in pancreatic cancer and to use a pharmacological strategy based on the activation of SIRT5, as an adjuvant to conventional gemcitabine-based therapy, in order to reduce tumour growth.

"SIRT5," says Antonello Mai of the Department of Chemistry and Technology of Drugs at Sapienza, "represents a mitochondrial sirtuin that has not yet been studied for its role in pancreatic ductal adenocarcinoma (PDAC)".

"This study," adds Dante Rotili of the same department, "revealed that SIRT5 is down-regulated both in human tissues with PDAC and in murine pancreatic tumours".

This down-regulation of SIRT5 modifies and activates the enzyme aspartate aminotransferase (AST/GOT1), allowing tumour cells to make greater use of glutamine, thereby promoting their growth and survival.

"A reduced level of SIRT5 expression," adds Marco Tafani of the Department of Experimental Medicine, "has also been associated with reduced survival of patients with pancreatic ductal adenocarcinoma.

Based on these results and continuing 20 years of research into the identification of small molecules as ligands of epigenetic targets, a specific activator of SIRT5 was synthesised, which, when administered with gemcitabine, was shown to reduce tumour growth in cell models in organoids obtained from human pancreatic carcinoma biopsies and in animal models.

"We have developed an innovative 'first in class' small molecule, a sirtuin 5 activator called MC3138," concludes Sergio Valente of the Department of Chemistry and Technology of Drugs.

The results obtained provide a new potential strategy based on the pharmacological activation of SIRT5 for treating pancreatic cancer patients with reduced expression of this sirtuin.

References:

Metabolic Rewiring by Loss of Sirt5 Promotes Kras-induced Pancreatic Cancer Progression. Tuo Hu, Surendra K. Shukla, Enza Vernucci, Chunbo He, Dezhen Wang, Ryan J. King, Kanupriya Jha, Kasturi Siddhanta, Nicholas J. Mullen, Kuldeep S. Attri, Divya Murthy, Nina V. Chaika, Ravi Thakur, Scott E. Mulder, Camila G. Pacheco, Xiao Fu, Robin R. High, Fang Yu, Audrey Lazenby, Clemens Steegborn, Ping Lan, Kamiya Mehla K, Dante Rotili, Sarika Chaudhary, Sergio Valente, Marco Tafani, Antonello Mai, Johan Auwerx, Eric Verdin, David Tuveson, Pankaj K. Singh. Gastroenterology. 2021 7:S0016-5085(21)03159-0. DOI: 10.1053/j.gastro.2021.06.045.