A New Therapeutic Target for Acute Leukemia
At the forefront of therapeutic advances in the treatment of 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 bone marrow cancer, which still kills three out of every four patients. This 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 bone marrow cancer, which is poorly treated and accounts for 1% of all cancers in France. Although treatments do exist—mostly based on intensive chemotherapy—most patients relapse. The 5-year survival rate today is only about one in four. “Moreover, chemotherapy is very harsh: half of the patients are ineligible because they could not tolerate it. And therapeutic progress has been limited for the past 50 years,” explains Guillaume Bossis, research director atthe Montpellier Institute of Molecular Genetics (University of Montpellier, CNRS). As part of the SUMOLAM project, which he has been leading for nearly 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 treatments. To fully understand this, it is important to know that this type of 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 involve blocking their proliferation (chemotherapy) or restoring their differentiation (differentiation therapy). “Our first discovery was to show that sumoylation is involved in how leukemias respond to these two types of therapies,” explains Guillaume Bossis. His team has demonstrated in vitro that inhibiting sumoylation enhances the effectiveness of these treatments. To explore the clinical application of this discovery, inhibitors of sumoylation enzymes must be identified. It is on this basis that the SUMOLAM project is launching.
The Medical Benefits of Peptides
To get the project off the ground, Guillaume Bossis brought in several teams. First, he collaborated with Muriel Amblard’s team at IBMM-Peptide, based at the University of Montpellier. This peptide chemist has demonstrated the effectiveness of peptides in blocking enzymes. Next, to identify the most effective peptides that could be considered for clinical use, he partnered with the Spanish team led by María Lois at the University of Barcelona, which has developed assays to analyze peptide activity. Over the past year and a half, the work of selecting and refining the peptides has allowed the team to test approximately 70 of them, identifying about ten that effectively function as inhibitors. For the best candidates, the team is seeking to further improve their efficacy by identifying peptide-enzyme bonds through X-ray crystallography, which will enable them to modify the peptide to achieve the strongest possible chemical interaction.
“Peptides are still rarely used in medical research,” explains the researcher, who highlights the advantages of these molecules over chemical active ingredients, thanks to their high bioavailability and low toxicity. While the project is progressing well in vitro, tests on cells followed by preclinical trials in a living organism are now needed to confirm the peptides’ activity. To this end, the team is collaborating with the Department of Clinical Hematology at Montpellier University Hospital, led by Guillaume Cartron, who 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 in the running to find a sumoylation inhibitor: the Japanese pharmaceutical company Takeda Pharmaceutical is currently conducting clinical trials for a chemical compound. But Guillaume Bossis is not discouraged; on the contrary: “We need more effective treatments given the ability of leukemia cells to resist treatment. A combination therapy using several molecules that target the same protein may help delay the development of resistance.”
In light of 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 a test to monitor the inhibitors’ efficacy. As for the development of a new treatment for acute myeloid leukemia, the team is prepared to see the project through to completion—even if no pharmaceutical company takes over the testing phase—by creating a dedicated startup.
* Sumoylation is a series of enzymatic reactions that result in the conjugation of the SUMO protein to thousands of other proteins, thereby altering their function and fate.