New effective combination therapy for paediatric T-acute leukaemia
The finding is based on a previous discovery made by Tampere University’s research group where the general tyrosine kinase inhibitor dasatinib was found to be effective in approximately one third of the tested patient samples. In the treatment of leukaemia, the efficacy of a single drug is usually lost quickly, so the new study searched for drug combinations that would have an enhanced synergistic effect with dasatinib. This was the case with temsirolimus, a drug that inhibits a parallel signalling pathway. The combination of the two drugs was more effective in eradicating leukaemia cells in cell culture, and zebrafish and mouse models than using a single drug.
“During the study, a new drug screening method for the rapid assessment of drug responses in leukaemia samples was developed and optimised in a zebrafish T-ALL model. In this screen, an effective drug combination was found, which was later confirmed by several cell line models, patient samples and mouse models,” says PhD Saara Laukkanen, the first author of the study.
“This has been a long project, taking 4–5 years, and as a result, we now understand the mechanism of action of these drugs at molecular level in T-ALL,” Laukkanen adds.
During the project, she spent six months as Visiting Researcher at Harvard Stem Cell Institute in Boston with Professor David Langenau’s research group, with whom the project was carried out.
“This is a promising new treatment option for T-acute leukaemia. The next step is to take the discovery into clinical practice for patients with relapsed or refractory disease via early phase clinical trials,” says Research Director Olli Lohi, MD, PhD, from Tampere University and Tays Hospital’s Cancer Centre.
“The development of precision treatments is slow and requires accurate knowledge of the molecular mechanisms that cause and maintain disease. Here we utilised a specific dependency of T-ALL cells on certain signalling routes that the combination of dasatinib and temsirolimus shuts off,” Lohi says.
The study was published in Blood, the most prestigious scientific journal in the field of hematology. In addition to researchers at Tampere University and Harvard Stem Cell Institute, researchers from the Universities of North Carolina, Eastern Finland and Helsinki also participated in the study.
Laukkanen S, Veloso A, Yan C, Oksa L, Alpert EJ, Do D, Hyvärinen N, McCarthy K, Adhikari A, Yang Q, Iyer S, Garcia SP, Pello A, Ruokoranta T, Moisio S, Adhikari S, Yoder YA, Gallagher K, Whelton L, Allen JR, Jin AH, Loontiens S, Heinäniemi M, Kelliher M, Heckman CA, Lohi O, Langenau DM. Combination therapies to target LCK tyrosine kinase and mTOR signaling in T-cell Acute Lymphoblastic Leukemia. Blood, painossa.
https://doi.org/10.1182/blood.2021015106
Photo: Daiga Ellaby / Unsplash
