New drug combination shows promise in treating colorectal cancer

Colorectal cancer is one of the most common tumors among people over the age of 50. Although it is known to develop from small lesions or polyps, its exact causes are unknown - only a few risk factors are known - and it is usually treated with surgery, chemotherapy and radiotherapy, or biological therapies. Now, a study by the University of Barcelona reveals that the combination of palbociclib and telaglenastat, two drugs with complementary actions, could help improve the clinical treatment of this type of cancer, the third most common worldwide. 

The new preclinical study, published in Nature's journal Oncogene, identifies for the first time a critical metabolic mechanism that would explain the resistance of cancer cells to the drug palbociclib in models of colorectal cancer.

The study was led by Marta Cascante, professor at the Department of Biochemistry and Molecular Biomedicine (Faculty of Biology) and member of the UB's Institute of Biomedicine (IBUB) and the CIBER Area for Liver and Digestive Diseases (CIBEREHD), and Timothy M. Thomson, researcher at the Molecular Biology Institute of Barcelona (IBMD-CSIC) and CIBEREHD, and current director of the Institute of Scientific Research and High Technology Services of Panama (INDICASAT).

The paper, whose first authors are researchers Míriam Tarrado-Castellarnau and Carles Foguet, involves the participation of researchers from the UB, IBUB and CIBEREHD, the Francis Crick Institute (United Kingdom) and CIBEREHD's Bioinformatics Platform.

When cancer cells are resistant to anticancer drugs

Palbociclib is a drug used in the treatment of advanced breast cancer that is positive for oestrogen receptor expression and negative for human epidermal growth factor receptor 2. Recently, clinical and preclinical trials of palbociclib have been extended to other types of cancer, such as colorectal cancer. Specifically, it belongs to a class of drugs that can inhibit two important proteins in cancer cells: cyclin-dependent kinases CDK4 and CDK6 (CDK4/6). These proteins play a key role in cell division and growth. Since this drug blocks the activity of protein kinases, it can help slow or stop the growth of cancer cells.

"In recent years, several mechanisms of cancer cell resistance to cyclin-dependent kinase inhibitors (CDKIs) have been identified, such as the overexpression of metabolic regulators such as glutaminase, described in a previous study by our research group", says Professor Marta Cascante, ICREA Academia researcher and head of the UB research group on Integrative Systems Biology, Metabolomics and Cancer, pioneer in metabolomics, fluxomics, and systems medicine applied to the design of new combination therapies for personalized medicine.

However, we had not yet determined whether these resistance mechanisms were the most appropriate therapeutic targets to combine with these inhibitors."

Míriam Tarrado-Castellarnau, First Author

In tumors, the treatment with palbociclib causes metabolomic reprogramming of colorectal cancer cells that survive the treatment. This metabolic adaptation ultimately enhances the metabolism of glutamine - an aminoacid with key functions in the body - and mitochondrial activity in the cell.

As part of this study, the team analysed the metabolic reprogramming in colorectal cancer cells exposed to palbociclib, which inhibits cyclin-dependent kinases 4 and 6 (CDK4/6), and telaglenastat, a selective inhibitor of glutaminase (an enzyme that catalyses the conversion of glutamine to glutamate and has altered expression in tumor processes).

A synergistic effect against tumor proliferation

The results reveal that a combined treatment with palbociclib and telaglenastat "prevents the metabolic reprogramming process of cancer cells that survive anticancer treatments with the first drug", says professor Marta Cascante.

A synergistic effect against tumor proliferation

"Palbociclib and telaglenastat induce complementary metabolic responses, making them particularly well suited to counteract the metabolic reprogramming caused by the other drug. Consequently, their combination causes a potent synergistic effect on tumor proliferation. In conclusion, resistance to palbociclib in cancer cells is avoided and cancer cell proliferation is reduced both in vitro and in vivo in animal models", explain Míriam Tarrado and Carles Foguet.

"In conclusion, we believe these findings justify a promising proposal to use this drug combination in clinical settings", the team stresses.

The graphic and informative summary of the new paper published in Oncogene is available in Catalan thanks to the Catalan Initiative for the Earth Biogenome Project (CBP), which promoted a repository model to make Catalan versions of science papers accessible from the original ones in English. The Initiative, created within the Catalan Society of Biology, a subsidiary of the Institute for Catalan Studies (IEC), receives support from IEC itself through the Biogenome-IEC project, funded by the Government of Catalonia.