Is it possible to identify, already in the initial diagnosis, signs that the cancer is going to return?

Sometimes, the retreat of a malignant disease is only a temporary situation: the cancer returns within a few months or years, and shows resistance to the drugs that were used in the first round. Does this happen because a number of malignant cells "learn" how to escape the effect of the chemotherapy treatment and start replicating themselves, or is it a hidden mechanism that lurks in the body from the beginning?

Dr Liran three, a doctor by training (MD-PhD) with a specialization in hematology, who joined the Weizmann Institute two years ago, revealed the presence of drug-resistant stem cells already in samples collected at the initial diagnosis of leukemia. The study, QHis results were published recently in the scientific journal Nature, reveals that there are two distinct groups of patients, carrying two different populations of resistant cells, which may ultimately lead to disease recurrence.

Dr. Shloush, who continues alongside his research to treat leukemia patients at the Princess Margaret Cancer Center in Toronto, Canada, and at the Rambam Hospital in Haifa, explains the starting point for the research that began about four years ago in the laboratory of Prof. John Dick at the University of Toronto : "In recent years it has been proven that many types of cancer, including leukemia, begin to develop from 'cancer stem cells' - cells that divide and differentiate into cells However, it was not clear whether these stem cells are also responsible for the disease returning, and if so, how exactly they are identified."

In order to investigate these questions, Shlosh and his colleagues took tissue samples from leukemia patients - at least two samples from each patient. The first was taken at the time of the original diagnosis, and the second - when the disease returned. With the help of Dr. Mark Minden and others in the laboratory, he performed three complete genome sequencing of the samples. After that, the researchers looked for signs of dominant mutations in the later sample that can confer survival to the cells, and checked whether these mutations also appeared in the initial sample. They assumed that cells in the original sample that contain Such mutations may carry in advance the seeds of disaster for the recurrence of the disease.

"With the help of the new ability to identify cells that cause the recurrence of the disease, and the genetic mutations involved in this, we will be able to improve the means of diagnosing leukemia and predicting its course"

After identifying possible candidates in both samples, the researchers tested some of them in a mouse disease model. The experiments provided clear support for the idea that the recurrence of leukemia is caused by an existing population of stem cells that survive chemotherapy. It was also found that most leukemia patients belong to one of two groups. In the first group, which includes the majority of patients (about 40%), there is a small minority of drug-resistant cells - about two resistant cells for every million leukemia cells. These are actual cancer stem cells, and Shloh says that despite their rarity, the results show that they are strong enough to promote treatment-resistant cancer in mice. In the second group there is a greater proportion of cells resistant to anti-cancer drugs - up to one in five. These are cells in the middle between unsorted stem cells and sorted mature cells called committed progenitors. The chance of disease recurrence is higher in this group. Indeed, when the researchers re-examined the early tissue samples taken at the initial diagnosis, and divided them into groups based on the appearance of the cells, they were able to predict which ones were most likely to have the disease return.

Cancer stem cells manage to survive the chemotherapy treatment, in part, because the chemotherapy targets cells that divide quickly - a hallmark of malignant cells - and thus misses the stem cells, whose rate of division is relatively slow. Furthermore, many of these stem cells carry "pumps" that are able to expel the drugs out of the cell membrane. "With the help of the new ability to identify cells that cause the recurrence of the disease, and the genetic mutations involved in this, we will be able to improve the means of diagnosing leukemia and predicting its course," says Shloosh. "It is to be hoped that in the future we will also be able to develop a means of warfare in the stem cells that carry these mutations, thereby preventing the recurrence of the cancer."

In a follow-up study in his laboratory in the Department of Immunology at the Weizmann Institute of Science, Three and his team are investigating why leukemic stem cells are resistant to drugs. Other laboratory research traces the earliest stages of the disease. They hope, among other things, that in the end, through these studies, they will open new ways for early diagnosis and treatment. Explains Shelus: "The common denominator between these research tracks is the cancer stem cells - pre-leukemic stem cells that cause the disease, and leukemic stem cells that cause its recurrence. We must understand exactly how these cells cause the disease, and the mechanisms that allow them to survive chemotherapy. Focus In these cells you will require us to develop completely new research and possibly therapeutic strategies."

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Among acute myeloid leukemia (AML) patients, the disease is expected to return in about 70% of cases even after successful treatment. In patients over the age of 60, the rate is even higher.