Periodic Reporting for period 4 - CLLCLONE (Harnessing clonal evolution in chronic lymphocytic leukemia)
Periodo di rendicontazione: 2023-01-01 al 2023-06-30
Chronic lymphocytic leukemia (CLL) is a common type of blood cancer in adults. Clinicians use a medicine called Ibrutinib to treat it. Ibrutinib is highly effective and is the standard treatment. It can be used by people who are getting treatment for the first time and for relapses of the disease.
Ibrutinib helps by killing cancer cells and redistributing of tissue-resident CLL cells into the blood. This makes the cancer shrink quickly, but it might increase the number of a certain kind of white blood cell temporarily.
Most people with CLL who get Ibrutinib see their cancer go into partial remission. This means there's still a tiny bit of the disease left in their blood, but it's not causing problems. This can last until the cancer becomes resistant to the treatment due to specific genetic changes. When that happens, the cancer starts growing again.
During remission, the cancer cells in the blood don't have these genetic changes, so it's like they found a different way to survive without the medicine. We're not sure how this works yet. Studying it might help us develop better treatments that can cure leukemia in the future.
Ibrutinib helps by killing cancer cells and redistributing of tissue-resident CLL cells into the blood. This makes the cancer shrink quickly, but it might increase the number of a certain kind of white blood cell temporarily.
Most people with CLL who get Ibrutinib see their cancer go into partial remission. This means there's still a tiny bit of the disease left in their blood, but it's not causing problems. This can last until the cancer becomes resistant to the treatment due to specific genetic changes. When that happens, the cancer starts growing again.
During remission, the cancer cells in the blood don't have these genetic changes, so it's like they found a different way to survive without the medicine. We're not sure how this works yet. Studying it might help us develop better treatments that can cure leukemia in the future.
Two studies called IOSI-EMA001 and IOSI-EMA003 looked at 102 patients with chronic lymphocytic leukemia (CLL) who were treated with Ibrutinib. We collected 702 samples from these patients over time. These studies were designed to detect patterns in the data. Out of these patients, 33 had a high risk of CLL, with some getting their first treatment and others who had relapsed. We kept track of these patients continuously until their disease got worse or they had to stop taking Ibrutinib because they couldn't tolerate it.
The genetic and clinical features of these 33 patients suggested they were at high risk for the disease. We examined their blood and used machine learning to find biological patterns. Before treatment and while the patients were in a state where there was still a bit of CLL left in their blood (but it wasn't causing problems), they couldn't find any genetic changes related to Ibrutinib resistance.
So, we looked at how Ibrutinib affected the cells in the body. We found that certain genes related to cell growth and energy production decreased after starting Ibrutinib. This suggested that the CLL cells were becoming less active. We also found that the cells that were still in the blood got smaller and less active over time. It was like the cells were trying to avoid the effects of Ibrutinib.
We also saw changes in certain genes related to a pathway called MAPK, which helps cells communicate. These genes became more active in the remaining CLL cells under Ibrutinib. To confirm this, we looked at a protein called Ki-67, which is related to cell growth, and found it decreased in these cells.
Next, we checked if these changes were due to genetic mutations. We tracked the mutations in the CLL cells and found that only a third of the patients had significant genetic changes. So, the majority of patients seemed to adapt to Ibrutinib without major genetic changes.
We also looked at how Ibrutinib affected the way genes are switched on and off, and we found some genes that were more active despite unchanged genetic features. These changes pointed to a pathway called ERK as a way the cells were avoiding the effects of Ibrutinib.
To test these findings, we used a cell line in the lab and found that blocking the ERK pathway along with Ibrutinib worked better than Ibrutinib alone. We then tested this in mice and saw that the combination of drugs helped control the cancer better and improved the mice's survival.
In summary, the research suggests that CLL cells survive Ibrutinib treatment by making non-genetic changes that allow them to use a pathway called ERK to stay alive.
The genetic and clinical features of these 33 patients suggested they were at high risk for the disease. We examined their blood and used machine learning to find biological patterns. Before treatment and while the patients were in a state where there was still a bit of CLL left in their blood (but it wasn't causing problems), they couldn't find any genetic changes related to Ibrutinib resistance.
So, we looked at how Ibrutinib affected the cells in the body. We found that certain genes related to cell growth and energy production decreased after starting Ibrutinib. This suggested that the CLL cells were becoming less active. We also found that the cells that were still in the blood got smaller and less active over time. It was like the cells were trying to avoid the effects of Ibrutinib.
We also saw changes in certain genes related to a pathway called MAPK, which helps cells communicate. These genes became more active in the remaining CLL cells under Ibrutinib. To confirm this, we looked at a protein called Ki-67, which is related to cell growth, and found it decreased in these cells.
Next, we checked if these changes were due to genetic mutations. We tracked the mutations in the CLL cells and found that only a third of the patients had significant genetic changes. So, the majority of patients seemed to adapt to Ibrutinib without major genetic changes.
We also looked at how Ibrutinib affected the way genes are switched on and off, and we found some genes that were more active despite unchanged genetic features. These changes pointed to a pathway called ERK as a way the cells were avoiding the effects of Ibrutinib.
To test these findings, we used a cell line in the lab and found that blocking the ERK pathway along with Ibrutinib worked better than Ibrutinib alone. We then tested this in mice and saw that the combination of drugs helped control the cancer better and improved the mice's survival.
In summary, the research suggests that CLL cells survive Ibrutinib treatment by making non-genetic changes that allow them to use a pathway called ERK to stay alive.
When patients are treated with Ibrutinib for chronic lymphocytic leukemia (CLL), some cells survive Ibrutinib treatment by making non-genetic changes. These cells find a way to stay active using a pathway called MAPK, that is a vulnerability of the cells surviving Ibrutinib. To make treatment even more effective, clinicians could use drugs that block the MAPK pathway along with Ibrutinib. We're going to test this idea in the lab and in clinical trials to see if it helps patients have deeper and longer-lasting responses to treatment.