Reference Detail

Ref Type

Journal Article

PMID

(35882450)

Authors

Sigaud R, Rösch L, Gatzweiler C, Benzel J, von Soosten L, Peterziel H, Selt F, Najafi S, Ayhan S, Gerloff XF, Hofmann N, Büdenbender I, Schmitt L, Foerster KI, Burhenne J, Haefeli WE, Korshunov A, Sahm F, van Tilburg CM, Jones DTW, Pfister SM, Knoerzer D, Kreider BL, Sauter M, Pajtler KW, Zuckermann M, Oehme I, Witt O, Milde T

Title

The first-in-class ERK inhibitor ulixertinib shows promising activity in MAPK-driven pediatric low-grade glioma models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Neuro-oncology			2022 Jul 27	566-579	Neuro Oncol

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	pleomorphic xanthoastrocytoma	predicted - sensitive	Trametinib + Ulixertinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Ulixertinib (BVD-523) and Mekinist (trametinib) had a synergistic effect on the induction of apoptosis in a pleomorphic xanthoastrocytoma cell line harboring BRAF V600E in culture (PMID: 35882450).	35882450
BRAF V600E	pleomorphic xanthoastrocytoma	sensitive	Navitoclax + Ulixertinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Ulixertinib (BVD-523) and Navitoclax (ABT-263) synergistically induced apoptosis in a pleomorphic xanthoastrocytoma cell line harboring BRAF V600E in culture, and improved the partial response rate compared to either drug alone in a zebrafish xenograft model (PMID: 35882450).	35882450
BRAF V600E	pleomorphic xanthoastrocytoma	sensitive	Ulixertinib + Vinblastine	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Ulixertinib (BVD-523) and Velban (vinblastine) inhibited proliferation and had a synergistic effect on induction of apoptosis in a pleomorphic xanthoastrocytoma cell line harboring BRAF V600E in culture (PMID: 35882450).	35882450
BRAF V600E	pleomorphic xanthoastrocytoma	predicted - sensitive	Selumetinib + Ulixertinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Ulixertinib (BVD-523) and Koselugo (selumetinib) inhibited proliferation in a pleomorphic xanthoastrocytoma cell line harboring BRAF V600E in culture (PMID: 35882450).	35882450
BRAF V600E	pleomorphic xanthoastrocytoma	sensitive	Binimetinib + Ulixertinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of Ulixertinib (BVD-523) and Mektovi (binimetinib) inhibited proliferation and had a synergistic effect on induction of apoptosis and inhibition of MAPK pathway activity in a pleomorphic xanthoastrocytoma cell line harboring BRAF V600E in culture, and improved the progressive disease/partial response ratio compared to either drug alone in a zebrafish xenograft model (PMID: 35882450).	35882450
BRAF V600E	pleomorphic xanthoastrocytoma	sensitive	Ulixertinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Ulixertinib (BVD-523) reduced metabolic activity and inhibited MAPK pathway activity in a pleomorphic xanthoastrocytoma cell line harboring BRAF V600E in culture, and inhibited tumor growth and improved survival compared to vehicle (48.5 days vs 30 days, respectively) in a xenograft model (PMID: 35882450).	35882450