New light is being shed on the mechanisms underlying the malignant transformation of lymphomas, paving the way for a promising therapeutic target, thanks to research conducted by a team led by Université de Montréal (UdeM) professor and Montreal Clinical Research Institute (IRCM) Tarik Möröy.
Director of the hematopoiesis and cancer research unit at the IRCM, affiliated with UdeM, Möröy worked with his team to discover that a specific enzyme, an RNA helicase called DDX3, is necessary for the development and progression of lymphoma.
Their study is published today in the journal Cancer Research.
Lymphoma often occurs in children or young adults and is characterized by the uncontrolled expansion of cells in our immune system called lymphocytes, causing large masses of tissue that often disfigure patients.
Such cancer is typically treated by surgically removing the tumour masses and then, in most cases, by chemotherapy, with high remission rates, above 80 per cent in children.
The problem with this treatment is its high toxicity, since chemotherapy uses powerful poisons in high doses that have the potential to kill all cells, whether cancerous or normal. And the treatment comes with serious side effects, including secondary cancers that occur later in life.
The impact on children with lymphoma is significant because they are still developing. The disease can return as early as six months after treatment, and a so-called "relapsing lymphoma" has a very poor prognosis, simply because the very powerful chemotherapeutic drugs used to fight it simply no longer work.
The importance of the DDX3 gene
New research done by Marion Lacroix, a PhD student in Möröy's laboratory, has addressed this problem and identified a potential solution.
Her experiments show that a specific strain of mice that spontaneously develops lymphoma no longer becomes ill or develop the disease later in life, when the DDX3 gene is genetically engineered out.
Because the DDX3 RNA helicase is an enzyme and its three-dimensional structure has several folds and pockets, it is an ideal target for small molecules that bind to these pockets and inhibit its activity.
With this in mind, Möröy laboratory team will now test combinations of inhibitors with conventional chemotherapeutic drugs, with the aim of reducing their dosage and thus the toxicity and severe side effects of lymphoma treatment – all particularly beneficial for children and young adults.
Tarik Möröy is the director of the hematopoiesis and cancer research unit at the IRCM. He is also a full research professor in the Department of Microbiology, Infectious Diseases and Immunology at Université de Montréal and an adjunct professor in the Division of Experimental Medicine at McGill University. Professor Möröy's work is supported by grants from the Canadian Institutes of Health Research, the Canada Foundation for Innovation and the Cancer Research Society. He held a Canada Research Chair (Tier 1) from 2007 to 2021 and was the IRCM’s fourth president and scientific director from 2006 to 2019. He is also a fellow of the Canadian Academy of Health Sciences (CAHS).
Marion Lacroix holds a master's degree in molecular biology and is a PhD student in Professor Möröy's laboratory at the IRCM, enrolled in the McGill University graduate program in experimental medicine. She came to Montreal from France to study at the IRCM and to undertake a research project on cancer for her doctoral thesis. She has already presented her work at several national and international conferences and has received several prestigious grants and awards. She is currently a recipient of a Cole Foundation Fellowship.
