Reference Detail

Ref Type

Journal Article

PMID

(37940144)

Authors

Friese-Hamim M, Ortiz Ruiz MJ, Bogatyrova O, Keil M, Rohdich F, Blume B, Leuthner B, Czauderna F, Hahn D, Jabs J, Jaehrling F, Heinrich T, Kellner R, Chan K, Tong AHY, Wienke D, Moffat J, Blaukat A, Zenke FT

Title

Novel Methionine Aminopeptidase 2 Inhibitor M8891 Synergizes with VEGF Receptor Inhibitors to Inhibit Tumor Growth of Renal Cell Carcinoma Models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	23	2	2024 Feb 01	159-173	Mol Cancer Ther

URL

Abstract Text

N-terminal processing by methionine aminopeptidases (MetAP) is a crucial step in the maturation of proteins during protein biosynthesis. Small-molecule inhibitors of MetAP2 have antiangiogenic and antitumoral activity. Herein, we characterize the structurally novel MetAP2 inhibitor M8891. M8891 is a potent, selective, reversible small-molecule inhibitor blocking the growth of human endothelial cells and differentially inhibiting cancer cell growth. A CRISPR genome-wide screen identified the tumor suppressor p53 and MetAP1/MetAP2 as determinants of resistance and sensitivity to pharmacologic MetAP2 inhibition. A newly identified substrate of MetAP2, translation elongation factor 1-alpha-1 (EF1a-1), served as a pharmacodynamic biomarker to follow target inhibition in cell and mouse studies. Robust angiogenesis and tumor growth inhibition was observed with M8891 monotherapy. In combination with VEGF receptor inhibitors, tumor stasis and regression occurred in patient-derived xenograft renal cell carcinoma models, particularly those that were p53 wild-type, had Von Hippel-Landau gene (VHL) loss-of-function mutations, and a mid/high MetAP1/2 expression score.

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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
TP53 wild-type VHL inact mut	renal cell carcinoma	sensitive	M8891 + Sunitinib	Preclinical - Pdx	Actionable	In a preclinical study, M8891 and Sutent (sunitinib) combination treatment resulted in improved tumor growth inhibition compared to monotherapies in patient-derived xenograft (PDX) models of TP53 wild-type renal cell carcinoma harboring VHL inactivating mutations (PMID: 37940144).	37940144
TP53 del	lung cancer	resistant	M8891	Preclinical - Cell culture	Actionable	In a preclinical study, knockout of TP53 conferred resistance to M8891 in a lung cancer cell line as demonstrated by loss of inhibition of colony formation in culture (PMID: 37940144).	37940144
TP53 wild-type VHL inact mut	renal cell carcinoma	sensitive	Cabozantinib + M8891	Preclinical - Pdx	Actionable	In a preclinical study, M8891 and Cometriq (Cabometyx, cabozantinib) combination treatment resulted in improved tumor growth inhibition compared to monotherapies in patient-derived xenograft (PDX) models of TP53 wild-type renal cell carcinoma harboring VHL inactivating mutations (PMID: 37940144).	37940144
TP53 wild-type VHL inact mut	renal cell carcinoma	sensitive	Axitinib + M8891	Preclinical - Pdx	Actionable	In a preclinical study, M8891 and Inlyta (axitinib) combination treatment resulted in improved tumor growth inhibition compared to monotherapies in patient-derived xenograft (PDX) models of TP53 wild-type renal cell carcinoma harboring VHL inactivating mutations (PMID: 37940144).	37940144