Reference Detail

Ref Type

Journal Article

PMID

(37828724)

Authors

Zhang W, Vaubel RA, Oh JH, Mladek AC, Talele S, Zhang W, Waller KL, Burgenske DM, Sarkaria JN, Elmquist WF

Title

Delivery versus Potency in Treating Brain Tumors: BI-907828, a MDM2-p53 Antagonist with Limited BBB Penetration but Significant In Vivo Efficacy in Glioblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	23	1	2024 Jan 03	47-55	Mol Cancer Ther

URL

Abstract Text

MDM2-p53 inhibition may be effective in glioblastoma (GBM). This study evaluates the pharmacokinetics/pharmacodynamics of BI-907828, a potent antagonist of MDM2, in GBM, and demonstrates a translational paradigm with a focus on a unified "Delivery - Potency - Efficacy" relationship in drug development for central nervous system(CNS) tumors. BI-907828 was tested for cytotoxicity and MDM2-p53 pathway inhibition. Systemic pharmacokinetics and transport mechanisms controlling CNS distribution were evaluated in mice. BI-907828 free fractions in cell media, mouse and human specimens were measured to determine "active" unbound concentrations. Efficacy measures, including overall survival and target expression were assessed in mouse orthotopic GBM xenografts. BI-907828 exhibited potent inhibition of MDM2-p53 pathway and promoted cell death in GBM TP53 wild-type cells. MDM2-amplified cells are highly sensitive to BI-907828, with an effective unbound concentration of 0.1 nmol/L. The CNS distribution of BI-907828 is limited by blood-brain barrier (BBB) efflux mediated by P-gp, resulting in a Kp,uu_brain of 0.002. Despite this seemingly "poor" BBB penetration, weekly administration of 10 mg/kg BI-907828 extended median survival of orthotopic GBM108 xenografts from 28 to 218 days (P < 0.0001). This excellent efficacy can be attributed to high potency, resulting in a limited, yet effective, exposure in the CNS. These studies show that efficacy of BI-907828 in orthotopic models is related to high potency even though its CNS distribution is limited by BBB efflux. Therefore, a comprehensive understanding of all aspects of the "Delivery - Potency - Efficacy" relationship is warranted in drug discovery and development, especially for treatment of CNS tumors.

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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
MDM2 amp TP53 wild-type	glioblastoma	sensitive	BI 907828	Preclinical - Cell line xenograft	Actionable	In a preclinical study, BI 907828 treatment inhibited viability of a cell line derived from a TP53 wild-type, MDM2-amplified glioblastoma patient-derived xenograft (PDX) model in culture and inhibited tumor cell proliferation, induced apoptosis, and resulted in improved median survival compared to vehicle treatment (10 mg/kg treatment: 218 days and 2 mg/kg treatment: 57 days vs vehicle: 28 days, p<0.0001) in the PDX model, despite limited blood-brain barrier penetration (PMID: 37828724).	37828724