The most common cancer in children is acute lymphoblastic leukemia (ALL). T-ALL leukemia, which emerges from early T lineage cells, has a worse prognosis than B-lineage ALL. Relapsed T-ALL has a terrible prognosis, and novel therapeutics are desperately needed.
A new combination of medications that is effective against T-ALL has been identified in a joint investigation between Tampere University's Faculty of Medicine and Health Technology in Finland, the Massachusetts General Research Institute, and the Harvard Stem Cell Institute.
The findings are based on a previous study by Tampere University researchers, who discovered that the generic tyrosine kinase inhibitor dasatinib was successful in roughly one-third of the patient samples studied.
Because the efficacy of a single medicine in the treatment of leukemia normally wears off rapidly, the current study looked for drug combinations that would have a stronger synergistic effect with dasatinib. This was the case with the medication temsirolimus, which blocks a parallel signaling route. In zebrafish and humans, a combination of the two medications was more successful than a single agent at eradicating leukemia cells.
"We established a new drug screening approach for assessing medication responses in zebrafish leukemia samples throughout this research. A useful drug combination was discovered in this screen, which was later confirmed by numerous cell line models, patient samples, and human leukemias generated in mice "The study's first author, Ph.D. Saara Laukkanen, adds
"This was a protracted experiment that lasted 4-5 years, and as a result, we now know the molecular mechanism of action of these medications in T-ALL," Laukkanen continues.
During the project, she worked as a Visiting Researcher in the Department of Pathology at Massachusetts General Hospital in Boston, where she worked with Professor David Langenau's research group. She collaborated closely with Ph.D. Alexandra Veloso, a Langenau research fellow and co-lead author on the paper.
"This is a promising new T-acute leukemia therapy approach. The next step is to use early phase clinical studies to translate the discovery into clinical practice for patients with relapsed or refractory disease "Olli Lohi, MD, Ph.D., from Tampere University and Tays Hospital's Cancer Centre, is the research director.
"Precision medicine takes time to develop because it necessitates a thorough understanding of the molecular pathways that create and maintain the disease. We took advantage of T-ALL cells' reliance on specific signaling pathways that are blocked by the combination of dasatinib and temsirolimus "Lohi explains.
The research was published in the journal Blood. Experts from the Universities of North Carolina, Eastern Finland, and Helsinki, as well as Tampere University and Harvard Stem Cell Institute researchers, took part in the study.
Saara Laukkanen, Alexandra Bacquelaine Veloso, Chuan Yan, Laura Oksa, Eric J. Alpert, Daniel Do, Noora Hyvärinen, Karin McCarthy, Abhinav Adhikari, Qiqi Yang, Sowmya Iyer, Sara P. Garcia, Annukka Pello, Tanja Ruokoranta, Sanni Moisio, Sadiksha Adhikari, Jeffrey A. Yoder, Kayleigh Mary Gallagher, Lauren Whelton, James R. Allen, Alexander Hai Jin, Siebe Loontiens, Merja Heinäniemi, Michelle A Kelliher, Caroline A. Heckman, Olli Lohi, David M Langenau. Combination therapies to inhibit LCK tyrosine kinase and mTOR signaling in T-cell Acute Lymphoblastic Leukemia. Blood, 2022; DOI: 10.1182/blood.2021015106