In one in five children with T-ALL, a type of leukemia, the cancer comes back after treatment: a recurrence. Chemotherapy often no longer works for these children, and their outcome is poor. New treatments are urgently needed to prevent a recurrence.
Some new therapies for T-ALL seem to work better when given with other drugs, for example with steroids such as prednisolone. Jordy van der Zwet, a PhD student in the Meijerink group at the Princess Máxima Center, looked at ways to maintain or increase the sensitivity to steroids in T-ALL.
Van der Zwet: ‘In my research I studied T-ALL leukemia cells in the lab, looking at chain reactions of molecules that determine the behavior of these cells. For example, cancer cells can switch on signals that promote their growth, or that make them insensitive to chemotherapy. I discovered that one such chain reaction, MAPK-ERK, is crucial in steroid insensitivity in T-ALL.’
He saw that the MAPK-ERK chain reaction switches off a protein called BIM. This protein normally instructs a cell to die. But in T-ALL with an active MAPK-ERK chain reaction, they survive and become insensitive to steroids.
Jordy van der Zwet: ‘We saw that a targeted drug, selumetinib, repaired the function of the BIM protein, causing the T-ALL cells to die. This effect was even stronger in leukemia cells treated with both selumetinib and a steroid such as predinisolone.’ Selumetinib blocks the MAPK-ERK chain reaction, so that the BIM protein signal stays switched on.
‘We now know which targeted drugs hold the most promise to improve treatment for children with T-ALL,’ says Van der Zwet. ‘We also have a better idea which children are eligible for clinical studies of targeted drugs in combination with steroids. The research is still at an early stage, but I hope it will lead to a more personalized, more effective treatment for children with (recurrent) T-ALL in the future.’
Jordy van der Zwet will defend his thesis, entitled ‘Aberrant IL7R signaling: the paths towards steroid resistance in pediatric T-cell acute lymphoblastic leukemia’, today (April 4) in the Utrecht University Academy Building. His promotor is Rob Pieters and his co-promotor is Jules Meijerink.