An international research team coordinated at the IRCM in Montréal found a possible alternative treatment for lymphoid leukemia. Led by Dr. Tarik Möröy, the IRCM's President and Scientific Director, the team discovered a molecule that represents the disease's "Achilles' heel" and could be targeted to develop a new approach that would reduce the adverse effects of current treatments such as chemotherapy and radiation therapy. The study's results are being published February 11 in the scientific journal Cancer Cell.
The researchers' results have direct implications for the treatment of acute lymphoblastic leukemia (ALL), one of the four most common types of leukemia. ALL is a cancer of the bone marrow and blood that progresses rapidly without treatment. Current treatments consist of chemotherapy and radiation therapy, which are both highly toxic and non-specific, meaning that they damage healthy cells as well as tumour tissues.
"Even when effective, patients can suffer dramatic side effects from these treatments," says Dr. Möröy, who is also Director of the Hematopoiesis and Cancer research unit at the IRCM and corresponding author of the study. "Therefore, they would directly benefit from an improved therapy that could reduce the necessary dose of radiation or chemotherapy, and thus their side effects, while maintaining the treatments' efficacy. Therapies that target specific molecules have shown great promise. This is why, for the past 20 years, I have been studying a molecule called Gfi1, which plays an important role in the development of blood cells and cancer."
When normal cells are transformed into tumour cells, the body responds by activating a tumour suppressor protein that induces cell death. Tumour cells must therefore counteract cell death in order to survive.
"With this study, we found that leukemic cells depend on the Gfi1 molecule for their survival," explains Dr. Cyrus Khandanpour, co-first author of the study and University Hospital physician at University Duisburg-Essen in Germany. "In fact, this molecule helps the malignant cells avoid death by hindering the activity of the tumour suppressor protein. Our results show that when Gfi1 is removed in mice that suffer from T-cell leukemia, the tumour disappears and the animals survive."
"Following this discovery, we wanted to test whether it could be used as a viable approach to treat leukemia in humans," adds Dr. Möröy. "We transplanted cells from a patient with T-cell leukemia into a mouse. We then inhibited the Gfi1 molecule using a commercially-available agent, and noticed that it stopped the expansion of human leukemia in the bone marrow, peripheral blood and spleen, without leading to adverse effects."
"These results are a significant indication that therapies targeting the molecule Gfi1 would work in human patients," says Dr. H. Leighton Grimes, co-corresponding author of the study from the Cincinnati Children's Hospital Medical Center. "In fact, if our results translate to patients, they could improve the prognosis of people suffering from lymphoid malignancies," adds Dr. James Phelan, the study's co-first author and recent PhD graduate in Dr. Grimes' laboratory.
"Our study suggests that a molecular-based therapy targeting Gfi1 would not only significantly improve response rates, but may also lower effective doses of chemotherapy agents or radiation, thereby reducing harmful side effects," concludes Dr. Khandanpour, who is also a visiting scientist at the IRCM. "Gfi1 represents an Achilles' heel for lymphoid leukemia and we are continuing to work so that our approach may soon move to clinical trials."
About acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is one of the four most common types of leukemia and affects blood cells and the immune system. The disease develops when immature white blood cells are overproduced in the bone marrow, crowd out normal cells, and eventually spread to other organs. Acute refers to the relatively short time course of the disease, as it can be fatal in as little as a few weeks if untreated.
According to the Leukemia & Lymphoma Society of Canada, ALL is the most common type of cancer in children from one to seven years old, and the most common type of leukemia in children from infancy up to age 19. Four out of five children with ALL are cured of their disease after treatment. The number of adults and their remission lengths have grown significantly over the past 30 years. An estimated 4,800 people in Canada were expected to develop leukemia in 2010.
- Cyrus Khandanpour, James D. Phelan, Lothar Vassen, Judith Schütte, Riyan Chen, Shane R. Horman, Marie-Claude Gaudreau, Joseph Krongold, Jinfang Zhu, William E. Paul, Ulrich Dührsen, Bertie Göttgens, H. Leighton Grimes, Tarik Möröy. Growth Factor Independence 1 Antagonizes a p53-Induced DNA Damage Response Pathway in Lymphoblastic Leukemia. Cancer Cell, 2013; 23 (2): 200 DOI: 10.1016/j.ccr.2013.01.011
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