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000180790 1001_ $$0P:(DE-He78)a5e60710c7515b3e1de74ced6928a9dd$$aSigaud, Romain$$b0$$eFirst author$$udkfz
000180790 245__ $$aThe first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models.
000180790 260__ $$aOxford$$bOxford Univ. Press$$c2023
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000180790 500__ $$a#EA:B310#EA:B062#EA:B360#LA:B062#LA:B310# / 2023 Mar 14;25(3):566-579
000180790 520__ $$aPediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors.We investigated the anti-tumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAF V600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing.Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of anti-proliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival.These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.
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000180790 650_7 $$2Other$$aBH3-mimetics
000180790 650_7 $$2Other$$aERK inhibitor
000180790 650_7 $$2Other$$aMAPK inhibitor
000180790 650_7 $$2Other$$apediatric low-grade glioma
000180790 650_7 $$2Other$$asynergism
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000180790 7001_ $$0P:(DE-He78)2b12a7cfc604eb9816670e995f7af508$$aBenzel, Julia$$b3$$eFirst author$$udkfz
000180790 7001_ $$0P:(DE-He78)bb01d83eec5ee7af4d816d0e9fd547a4$$avon Soosten, Laura$$b4$$eFirst author$$udkfz
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000180790 7001_ $$0P:(DE-He78)f08873535c440e3ce033c84d5786f70f$$aNajafi, Sara$$b7$$udkfz
000180790 7001_ $$0P:(DE-He78)32e22d1c8416af3f2a612da9121f2c05$$aAyhan, Simay$$b8$$udkfz
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000180790 7001_ $$0P:(DE-He78)e25b60d9259f2123f28e410cfdc6b0a4$$aBüdenbender, Isabel$$b11$$udkfz
000180790 7001_ $$0P:(DE-He78)5ebf27c73a3f0b66abe1c471997cebb8$$aSchmitt, Lukas$$b12$$udkfz
000180790 7001_ $$00000-0001-8583-7181$$aFoerster, Kathrin I$$b13
000180790 7001_ $$00000-0002-2190-1698$$aBurhenne, Jürgen$$b14
000180790 7001_ $$00000-0003-0672-6876$$aHaefeli, Walter E$$b15
000180790 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b16$$udkfz
000180790 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b17
000180790 7001_ $$0P:(DE-He78)a6b5fcabf661bef95109dbee87dc5271$$avan Tilburg, Cornelis Martinus$$b18$$udkfz
000180790 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b19$$udkfz
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000180790 7001_ $$aKnoerzer, Deborah$$b21
000180790 7001_ $$00000-0002-3223-1466$$aKreider, Brent L$$b22
000180790 7001_ $$aSauter, Max$$b23
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