TY  - JOUR
AU  - Sigaud, Romain
AU  - Rösch, Lisa
AU  - Gatzweiler, Charlotte
AU  - Benzel, Julia
AU  - von Soosten, Laura
AU  - Peterziel, Heike
AU  - Selt, Florian
AU  - Najafi, Sara
AU  - Ayhan, Simay
AU  - Gerloff, Xenia
AU  - Hofmann, Nina
AU  - Büdenbender, Isabel
AU  - Schmitt, Lukas
AU  - Foerster, Kathrin I
AU  - Burhenne, Jürgen
AU  - Haefeli, Walter E
AU  - Korshunov, Andrey
AU  - Sahm, Felix
AU  - van Tilburg, Cornelis Martinus
AU  - Jones, David
AU  - Pfister, Stefan
AU  - Knoerzer, Deborah
AU  - Kreider, Brent L
AU  - Sauter, Max
AU  - Pajtler, Kristian
AU  - Zuckermann, Marc
AU  - Oehme, Ina
AU  - Witt, Olaf
AU  - Milde, Till
TI  - The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models.
JO  - Neuro-Oncology
VL  - 25
IS  - 3
SN  - 1522-8517
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2022-01552
SP  - 566-579
PY  - 2023
N1  - #EA:B310#EA:B062#EA:B360#LA:B062#LA:B310# / 2023 Mar 14;25(3):566-579
AB  - Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors.We investigated the anti-tumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAF V600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing.Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of anti-proliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival.These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.
KW  - BH3-mimetics (Other)
KW  - ERK inhibitor (Other)
KW  - MAPK inhibitor (Other)
KW  - pediatric low-grade glioma (Other)
KW  - synergism (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35882450
DO  - DOI:10.1093/neuonc/noac183
UR  - https://inrepo02.dkfz.de/record/180790
ER  -