A new therapeutic target for acute leukemia
At the forefront of advanced therapeutic advances for treating acute myeloid leukemia, the SUMOLAM project is on the verge of identifying a peptide capable of improving the effectiveness of treatments. This is a major medical challenge for this type of bone marrow cancer, which still kills three out of four patients. The project has received support from I-SITE MUSE as part of its 2018 research program.
Finding a new treatment for acute myeloid leukemia. The medical challenge is considerable for this poorly treated bone marrow cancer, which accounts for 1% of cancers in France. Although treatments exist, mainly based on intensive chemotherapy, most patients relapse. The five-year survival rate is currently only about one in four. "In addition, chemotherapy is very harsh: half of patients are not eligible because they cannot tolerate it. And therapeutic progress has been limited for 50 years," explains Guillaume Bossis, director of research atthe Institute of Molecular Genetics in Montpellier (University of Montpellier, CNRS). As part of the SUMOLAM project, which he has been leading for almost two years, he is working on a new therapeutic target to combat these types of leukemia.
This target is sumoylation*, a series of enzymatic reactions that block treatment. To understand this properly, it is important to know that this leukemia is linked to the proliferation of immature blood cells and a blockage in their differentiation. This phenomenon prevents the normal production of red blood cells, white blood cells, and platelets. Possible treatments for the disease consist of blocking their proliferation (chemotherapy) or restoring their differentiation (differentiation therapy). "Our first discovery was to show that sumoylation is involved in the response of leukemias to these two types of therapies," explains Guillaume Bossis. His team proved in vitro that inhibiting sumoylation enhances the action of these treatments. To consider the clinical application of this discovery, sumoylation enzyme inhibitors must be found. This is the basis for the SUMOLAM project.
The medical interest of peptides
To set up the project, Guillaume Bossis surrounded himself with several teams. First, Muriel Amblard's team at IBMM-Peptide, based at the University of Montpellier. This peptide chemist demonstrated the effectiveness of peptides in blocking enzymes. Next, to find the most effective peptides for clinical use, he teamed up with María Lois's Spanish team at the University of Barcelona, which has developed tests to analyze peptide activity. Over the past year and a half, the work of selecting and improving peptides has enabled around 70 to be tested, resulting in the identification of around ten that perform well as inhibitors. For the best candidates, the team is seeking to further improve their effectiveness by identifying peptide-enzyme bonds using crystallography, which will enable the peptide to be modified to achieve the strongest possible chemical interaction.
"Peptides are still rarely used in medical research," explains the researcher, who points out the advantages of these molecules over chemical active ingredients, thanks to their good bioavailability and low toxicity. While the project is progressing well in vitro, tests on cells and then preclinical trials in a living organism must now confirm the activity of the peptides. To this end, the team is working in collaboration with the Clinical Hematology Department at Montpellier University Hospital, headed by Guillaume Cartron, which is providing access to patient cells from the HémoDiag sample bank. These cells can be transplanted into mice for in vivo testing.
Two companion patents filed
In the race for medical research, another player is competing to find a sumoylation inhibitor: Japanese laboratory Takeda Pharmaceutical is currently conducting clinical trials on a chemical molecule. But Guillaume Bossis is not discouraged. On the contrary, he believes that "the proliferation of effective treatments is necessary in light of leukemia cells' ability to resist treatment. A therapy combining several molecules targeting the same protein may help delay these resistance phenomena."
Given the progress made in their research, the team plans to file a patent for a sumoylation inhibitor by the end of the project. Two companion patents have already been filed, including one for a test to monitor the effectiveness of the inhibitors. As for the application of a new treatment for acute myeloid leukemia, the team is prepared to see it through to the end if no other laboratory takes over the testing phase, by creating an ad hoc start-up.
* Sumoylation is a series of enzymatic reactions that lead to the conjugation of the SUMO protein onto thousands of proteins to modify their function and fate.