New leukemia therapies based on genetic insights

Leukemia – blood cancer – is a complex disease. Leukemia cells can assume hundreds of different genetic forms. Thoas Fioretos, a Wallenberg Clinical Scholar in Lund, is mapping genetic mutations in leukemia cells, and trying to understand which of them cause disease. This knowledge may lead to more accurate diagnoses and new therapies.

Thoas Fioretos

Consultant and Professor of Clinical Genetics

Wallenberg Clinical Scholar 2018

Institution:
Lund University

Research field:
Acute leukemia, cancer genetics

Strictly speaking, leukemia is not a single disease; it is an umbrella term for several diseases. There is a chronic form that can usually be kept at bay with drugs. But there are also acute forms occurring in both adults and children. Children usually survive, but the mortally rate among adults is high.

All cancers are due to genetic changes occurring in the body’s cells. Gene mapping has shown that leukemia in particular involves hundreds of changes, which differ from one patient to another.

“Some of the changes drive the disease. These are the ones that new therapies must target,” Fioretos says.

He is a consultant at Skåne University Hospital and a professor at the Division of Clinical Genetics at Lund University. As a Wallenberg Clinical Scholar, he is intensifying his analyses of blood cancer cells. He describes it as building a detailed map for health care providers and for drug development. Cancer cell DNA already provides considerable information on which to base the choice of therapy. A milder form of cancer, for instance, can be treated more gently than an aggressive form of leukemia.

“It’s become less common to combine the roles of researcher and doctor – perhaps because medical care providers find themselves working under ever-growing pressure. This makes an initiative like Wallenberg Clinical Scholars all the more essential. The funding will enable my team to address important and challenging scientific issues more quickly and more effectively.”

Cancer stem cells the key

A key element in Fioretos’ work is to identify and study “mother cells” – cancer stem cells. These are cells in bone marrow that produce all the other cancer cells. They are resistant to most treatments currently available, and may comprise a mere thousandth part of all diseased cells. If they could be eradicated, the disease would disappear.

Fioretos is focusing on the surface of cancer stem cells. All cells have molecules on their surface capable of facilitating entry to the cell, as “flags” or pathways. If surface molecules that are unique to cancer stem cells can be identified, and antibodies that bind to them can be synthesized, those antibodies will trigger the immune system into destroying the cell. Fioretos and his colleagues are also testing how the stem cells react to different substances produced by the body itself. A substance that causes the cells to grow may become a target for new drugs.

“A few years ago we managed to produce a substance that is now being developed by a pharmaceutical company, so we know that it is actually possible to make drugs based on our studies. And there’s no time to be wasted.”

Unique genetic features of the stem cells may also enable better monitoring of leukemia patients. Health care staff would be able to analyze blood samples to search for cancer stem cell “imprints”, enabling them to see whether the latest treatment had been successful, or whether a relapse was impending.

“Why do some patients respond well to treatment, but not others? Why do some patients suffer a relapse after five years? By monitoring patients and searching back in time through our DNA data, we can see the cause and effect of various patterns. We’re drawing a map of something that is largely unknown.”

A chance occurrence

The son of Greek and Austrian parents, Fioretos grew up in Sweden. He enjoyed most school subjects, and decided to follow in his father’s footsteps and become a doctor. But straight A’s in all subjects were needed to get into medical school in Sweden. He didn’t make it at the first attempt, and was not prepared to wait, so he moved to Germany to study medicine there. This enabled him to transfer to the medicine program in Sweden later on.

He had originally planned to become a brain surgeon, but gradually became more interested in other fields. One day he found himself by chance at an open lecture on cancer genetics, and realized he had discovered a fascinating new subject. He went up to the lecturer’s department and asked if there were any research projects he could join.

“In those days there were no boundaries at all between the academic world and health care – it was easy to move between the two. And cancer research was going through a tremendously dynamic phase,” Fioretos says.

Nowadays he spends 70 percent of his time working on research, and 30 percent at the hospital. He is responsible for reporting the results of leukemia patients’ DNA analyses to their doctors, but he also meets patients suffering from a wide range of genetic diseases, not only leukemia. His role is then to provide “genetic guidance” to patients and their families. If a patient develops a hereditary disease, their siblings and children may need to decide whether they should be tested to see if they bear the same gene. Guidance from care providers is essential and ethnically challenging. Fioretos explains:

“I think I benefit enormously from being both a researcher and a clinician. As a doctor, you pose somewhat different scientific questions in your research – questions that perhaps have a greater bearing on problems experienced by patients. And as a researcher you are trained to interpret research findings, quickly familiarize yourself with new findings, and put difficult questions. These aspects are of great help to a practicing doctor.”

Text Lisa Kirsebom
Translation Maxwell Arding
Photo Magnus Bergström