Understanding Resistance to Cancer Therapies

Understanding Resistance to Cancer Therapies
Pancreatic cancer cells (Credit: Medicalnewstoday)

Resistance to existing cancer therapies was one of the main themes of Toulouse Onco Week from February 1-5 in Southern France. We spoke with Vera Pancaldi, laureate of the Chair of bioinformatics in Oncology of the CRCT. According to her, immunotherapy might become the standard of care at some point.

 

MedicalExpo Magazine: Can you describe your work?

Vera Pancaldi: I arrived in Toulouse in September 2018 and the idea was to start a computational biology group at the CRCT. There were many people with expertise in oncology or biology, but not a lot of people with expertise in modern methods for dealing with big data and how to integrate different types of data for medicine and biology. So I was given this industrial chair which is generously funded by the Fondation Toulouse Cancer Santé, Pierre Fabre and Inserm for five years.

I’m studying immuno-oncology which is trying to understand how to use the cells of the immune system to defeat cancer cells, rather than just trying to kill the cancer cells with chemotherapy. Chemotherapy can destroy many of the good cells as well, leading to side effects that can be harmful to patients sometimes. Often, there are already immune cells inside a tumor, you just have to wake them up so they will be able to kill the cancer cells. Immunotherapy is a revolution in oncology, but so far we haven’t had a clear mechanistic view of what is happening inside the tumor.

Inside the tumor, you have many different cell types, but it is hard to understand which interactions between them actually lead to the tumor growing or, in the case of therapies that work, to the tumor shrinking or disappearing. When I came to Toulouse, my aim was to bring a computational biology perspective to all of these questions. Immunotherapy can be very successful in around 20 to 30% of patients but unfortunately in many other patients it works initially but then resistance develops and it ends up being a treatment that is not curative.

“Immunotherapy can be very successful in around 20 to 30% of patients but unfortunately in many other patients it works initially but then resistance develops and it ends up being a treatment that is not curative.”

MedicalExpo Magazine: Why have you been working on pancreatic cancer specifically? 

Vera Pancaldi: Pancreatic cancer is one of the worst cancers because not much progress has been made and the five-year relative survival rate is still lower than 10%. Other cancers like breast cancer are very common and can be cured very well. Despite not being a common disease, pancreatic cancer is one of the first causes of death by cancer similar to lung cancer, which is much more common. Patients are diagnosed too late and unless the tumor is small enough to be removed, not many therapies work.

 

“Resistance is an interesting and complex problem because there are multiple sources and different types of resistance.” (Credit: DDM Archives)

Immunotherapy has not been working at all for this type of cancer. Most immunotherapies being developed now are based on re-activating T-cells that are asleep in the tumor. But the problem is that sometimes there are no immune cells inside the tumor that you can try to reactivate to kill the cancer. So part of my work is trying to understand why there are cases when you do have an army of these T-cells and other cases when it seems that other immune cells are present and preventing the T-cells from getting into this cancer.

I’m working on a mathematical model to understand the interactions between the different cell types in the tumor. If we have an extended simulation of this model we might be able to see which type of therapy might be combined with immunotherapy to actually make it work on pancreatic cancer. We use a simple model where each cell is like a person with a specific behavior. So we study the cells, we look at what they do and then we reproduce these behaviors in our simulation. The idea is to start from the rules that each cell follows, which we can identify from experiments, and then study the emergent behaviors of the mass of cells together.

“Most immunotherapies being developed now are based on re-activating T-cells that are asleep in the tumor. But the problem is that sometimes there are no immune cells inside the tumor that you can try to reactivate to kill the cancer.”

MedicalExpo Magazine: Where does the resistance to therapies come from?

Vera Pancaldi: Resistance is an interesting and complex problem because there are multiple sources and different types of resistance. We think that it is quite likely for the cell to develop resistance when there is only one attack. Cancer cells simply find a way to evade it by changing their behavior or even changing their characteristics. Along with chemotherapy, many cancers today are treated with “targeted therapies” that hit one specific weak point in the cancer cell. Very often these therapies generate resistance as the cancer’s weak points change. If we were able to provide multiple attacks at the same time it would work better. The power of combinatorial therapy is to use two drugs to attack the tumor so that it will be more difficult for it to escape.

 

“If we were able to understand the origin of the fight between the immune cells and the cancer cells, and if we could switch off this fight, then it would be less likely for the cancer to develop resistance.” (Credit: iStock)

If we were able to understand the origin of the fight between the immune cells and the cancer cells, and if we could switch off this fight, then it would be less likely for the cancer to develop resistance. The fact that there is a competition between the cancer cells and the immune cells is what makes the cancer cells evolve so fast, through strong selection pressure. It is a process similar to Darwinian evolution, if a population is in a difficult situation and there is very strong pressure to survive, individuals are going to be much more motivated to diversify.

“The fact that there is a competition between the cancer cells and the immune cells is what makes the cancer cells evolve so fast, through strong selection pressure. It is a process similar to Darwinian evolution, if a population is in a difficult situation and there is very strong pressure to survive, individuals are going to be much more motivated to diversify.”

No one knows the correct way to safety so each tries their own way. In the case of cancer, this implies changes in the phenotypes of cells (their behavior) but also in the genes (instructions that determine the cell’s characteristics). The result is that cancer cells will fight harder. If we were able to convince the cancer cells that there is no point fighting then hopefully cancer cells would stop looking for ways to escape, resistance would not develop and a single type of attack could be enough to stop the tumor from growing.

MedicalExpo Magazine: Will immunotherapy one day replace chemotherapy?

Vera Pancaldi: It is already replacing chemotherapy in many different places, it is especially offering hope to people chemotherapy doesn’t work for. People with advanced melanoma didn’t use to have a choice, they were considered incurable; now they get immunotherapy and some of them can live much longer. On melanoma, the results of immunotherapy are absolutely incredible. On lung cancer, which is also a very deadly disease, it’s working quite well—but quite well doesn’t mean on all the patients.

So for many cancers, immunotherapy might become the standard of care at some point but we need to understand why it only works on 20 to 30% of patients. With our mathematical models, we are trying to understand which people it might work for and which people it might not so that we can treat only the patients who will benefit from it.

“For many cancers, immunotherapy might become the standard of care at some point but we need to understand why it only works on 20 to 30% of patients.”

MedicalExpo Magazine: Does immunotherapy have any side effects?

Vera Pancaldi: Unlike chemotherapy, immunotherapy does not have many side effects, but there are some. Boosting the immune system can increase the risk for autoimmune diseases that are permanent conditions which can be very debilitating. There are also some rare cases of serious side effects, but we are still figuring out all the details. One problem with these therapies is that they are very expensive and it is fundamental to find out which patients respond by better understanding the interactions between cancer cells and surrounding cells.

 

 

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