Defeating leukemia cells by depriving them of energy

Date:
February 17, 2022
Source:
Universite' de Gene`ve
Summary:
Acute myeloid leukemia, which affects blood and bone marrow cells,
is a particularly dangerous form of cancer. More than half of
patients under the age of 60 die. This proportion rises to 85% for
patients over 60. A team has now identified a previously unknown
mechanism that could lead to the development of new therapies. The
selective activation of AMPK, a key enzyme in the energy balance
of tumor cells, would indeed lead to their death by triggering the
cells stress response. Moreover, the scientists have successfully
exploited this energy gap in an animal model of the disease: a
combination of two drugs -- one of which is already on the market
-- has indeed shown promise. However, their effectiveness has yet
to be confirmed on leukaemia stem cells, which have the ability
to escape many treatments to restart tumor growth.



FULL STORY ========================================================================== Acute myeloid leukaemia, which affects blood and bone marrow cells, is a particularly dangerous form of cancer. More than half of patients under
the age of 60 die. This proportion rises to 85% for patients over 60. A
team from the University of Geneva (UNIGE), Switzerland, and from Inserm,
in France, have identified a previously unknown mechanism that could lead
to the development of new therapies. The selective activation of AMPK,
a key enzyme in the energy balance of tumour cells, would indeed lead
to their death by triggering the cells stress response. Moreover, the scientists have successfully exploited this energy gap in an animal model
of the disease: a combination of two drugs - - one of which is already
on the market -- has indeed shown promise. However, their effectiveness
has yet to be confirmed on leukaemia stem cells, which have the ability
to escape many treatments to restart tumour growth. These results can
be found in the journal Cell Reports.


========================================================================== Je'ro^me 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 Le'man (SCCL)
and a professor at Universite' 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 Je'ro^me 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,
Je'ro^me 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 Je'ro^me 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 Je'ro^me 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
Je'ro^me 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/Le'on Be'rard Centre) and the Toulouse Cancer Research
Center (Inserm/CNRS/Toulouse III -- Paul Sabatier University) ========================================================================== Story Source: Materials provided by Universite'_de_Gene`ve. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Adrien Grenier, Laury Poulain, Johanna Mondesir, Arnaud Jacquel,
Claudie
Bosc, Lucille Stuani, Sarah Mouche, Clement Larrue, Ambrine Sahal,
Rudy Birsen, Victoria Ghesquier, Justine Decroocq, Fetta Mazed,
Mireille Lambert, Mamy Andrianteranagna, Benoit Viollet, Patrick
Auberger, Andrew A. Lane, Pierre Sujobert, Didier Bouscary,
Jean-Emmanuel Sarry, Jerome Tamburini. AMPK-PERK axis represses
oxidative metabolism and enhances apoptotic priming of mitochondria
in acute myeloid leukemia. Cell Reports, 2022; 38 (1): 110197 DOI:
10.1016/j.celrep.2021.110197 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220217102036.htm

--- up 10 weeks, 5 days, 7 hours, 13 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)