Defeating leukemia cells by depriving them of energy

Jérôme Tamburini, an associate professor in the Department of Medicine and in the Translational Research Centre in Onco-Haematology (CRTOH) of UNIGE Faculty of Medicine and at the Swiss Cancer Center Léman (SCCL) and a professor at Université de Paris, is working on the energetic mechanisms of tumour cells in acute myeloid leukaemia. A cell signalling pathway called AMPK is of particular interest to him. "AMPK is the main detector of the cells energy level," explains Jérôme Tamburini. "This pathway is activated when energy is lacking and initiates the degradation of certain nutrients to produce the necessary energy -- a process called catabolism. As without energy, no cell can survive, could it be possible to selectively manipulate this mechanism in tumour cells to cause their destruction, while preserving healthy cells?"

In 2015, Jérôme Tamburini and his colleagues at Inserm in Paris participated in the development with the GlaxoSmithKline (GSK) laboratory of a pharmacological component -- GSK621 -- which proved to be an excellent activator of AMPK in vitro. "After this initial proof of principle, we had to decipher the biochemical mechanisms at work in order to understand them in detail, and in particular which cellular pathways did GSK621 activate in leukaemia cells, the first step in hoping to exploit this phenomenon for therapeutic purposes," explains Jérôme Tamburini.

An effective combination of two drugs

The first step was to perform a gene expression analysis of human tumour cells, which identified an enzyme, PERK, particularly activated in response to the presence of GSK621. This is a key element in the stress response of the endoplasmic reticulum, an intracellular structure specialised in the metabolism of proteins and lipids. "The activation of AMPK thus triggers the activation of PERK, followed by a chain of reactions leading to apoptosis, the programmed death of the cell," explains Jérôme Tamburini. "In addition, the activation of AMPK by GSK621 sensitises the cells to the effects of another pharmacological drug, the venetoclax, which is now widely used to treat acute myeloid leukaemia, although with limited effectiveness when used alone."

The scientists then combined the two drugs in mice carrying human tumour cells, and found that this combination controlled tumour development much more effectively than in monotherapy. While GSK621 was not designed to be a drug, other products are currently in clinical trials to combat metabolic diseases, which activate the AMPK pathway. "Understanding the mechanism involved has brought to light potential therapeutic targets that were previously unknown," explains Jérôme Tamburini. "We will now be able to review all the drugs known to have an effect on these pathways and determine which combinations would be the most effective."

What about leukaemic stem cells?

Leukaemic stem cells consists in a small population of cells within the tumour that can only be detected by their ability to spread again the tumour after an initially successful treatment. The main cause of relapse, these cells are sensitive to very few of the therapies usually used in leukaemia. Furthermore, evidence is still lacking to determine the effect that massive activation of AMPK would have on them. "Before testing drug combinations targeting this AMPK/PERK mechanism in human beings, we need to determine their effect on leukaemic stem cells," the authors conclude.

Several laboratories were involved in this research, including Institut Cochin (Inserm/CNRS/University of Paris), the Cancer Research Center of Lyon (Inserm/CNRS/Claude Bernard Lyon 1 University/Léon Bérard Centre) and the Toulouse Cancer Research Center (Inserm/CNRS/Toulouse III -- Paul Sabatier University)