People with acute myeloid leukaemia (AML) have bleak prospects, but new research shows that studying the profiles of the proteins in patients’ cancer cells at diagnosis may help doctors predict whether the cancer will return or not.
New research indicates that doctors can examine the profiles of the proteins in a cancer cell in connection with diagnosing a person with AML and use the result to determine whether the cancer is likely to return after intensive chemotherapy treatment ends.
In addition to the obvious diagnostic potential for stratifying the risk of and managing patients, the discovery can also be used to find drugs that can target the proteins present in greater or lesser amounts among relapsed patients.
Finally, the discovery paves the way for doctors to identify high-risk patients, who should receive more intensive therapy, such as stem cell transplantation, from the start.
“Patients with AML who relapse express proteins differently than patients who are cured. These protein markers can potentially be used to identify patients at high risk of relapse, who can therefore be treated more intensively right from the start: for example, with allogeneic stem cell transplantation,” explains the first author, Elise Aasebo, postdoctoral fellow, Department of Clinical Science, University of Bergen, Norway.
The research has been published in Cancers.
Analysed cancer cells from 41 AML patients at diagnosis
The prognosis for people with AML is generally unfavourable, and only 40–50% of patients survive long term. One reason for this high mortality rate is that many people relapse after treatment ends. Predicting which patients might relapse and who might be cured has also been difficult.
Genetic markers such as the FLT3-ITD mutation can help predict the prognosis of AML to some extent, but Elise Aasebo thinks that something better is required.
In the new study, the researchers collected samples of cancer cells from 41 AML patients at diagnosis and then analysed the profiles of the proteins in the cells before treatment began.
Then the researchers analysed whether the levels of and the interrelationships between the proteins differed according to whether the patients later relapsed or not.
“Some proteins have specific functions in the body, and phosphoproteomes regulate the function of other proteins. The proteins are a proxy for what the cells are doing and what signalling pathways are activated when the cells develop into cancer cells. The rationale behind the study was that relapsed and relapse-free patients would differ,” explains Tanveer Singh Batth, postdoctoral fellow at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
Tanveer Singh Batth and colleagues from the Novo Nordisk Foundation Center for Protein Research contributed to the analysis of the enormous quantity of data obtained from studying a cell’s total protein expression.
351 differentially expressed proteins related to risk of relapse
Of the 41 participants, 25 experienced that the cancer returned after intensive chemotherapy, and 16 remained healthy.
The researchers examined the differences in protein expression and found that, of 6,781 proteins, 351 were differentially expressed with statistical significance between the relapsed and relapse-free groups.
The relapsed group had 210 upregulated proteins, and 141 proteins were downregulated relative to the relapse-free group.
In addition, the researchers identified 274 differentially regulated phosphorylated sites with statistical significance between the two groups.
“It was very interesting that, although the patients had considerable heterogeneity in the protein profiles, we still found some common denominators between most of the people who relapsed and those who remained relapse-free. Cancer cells from relapsed patients were associated with increased expression of the RNA-processing proteins. This applied to people who relapsed early and late,” says Elise Aasebo.
Developing a clinical assay
The goal of the research is to provide doctors with an assay to predict which patients will relapse and who will not, so that they can regulate treatment based on the results.
In addition, insight into the differences in protein expression may also be used to tailor treatment, enabling doctors to choose drugs to specifically target the proteins that are up- or downregulated among people at high risk of relapsing.
“The number of patients in this study was rather small, but the results point in an interesting direction and are worth investigating further,” says Tanveer Singh Batth.
Elise Aasebo therefore thinks that these results should be tested on a larger group of people with AML.
“The results must be validated to be clinically significant. We would like to test this on selected markers, in this case peptides, for which we will use a technique called parallel reaction monitoring to accurately analyse the quantity of numerous peptides very rapidly. If this succeeds, we can develop a clinical assay with some selected markers for rapidly analysing patient samples at diagnosis,” says Elise Aasebo.
If the results of an assay show that the person is at high risk of relapse, the hospital’s doctors must decide how to approach treatment to maximize the potential for cure.
“Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia” has been published in Cancers. Several co-authors are employed at the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen. Post.doc Maria Hernandez-Valladares from Department of Clinical Science at the University of Bergen is the other main author of the study.