Abstract A156: Preclinical activity of MDM2 antagonist RO6839921, a pegylated prodrug for intravenous administration

Abstract

Abstract The p53 tumor suppressor is a transcription factor that inhibits tumorigenesis by inducing cell cycle arrest or apoptosis in response to diverse stresses. In normal cells, p53 levels are tightly controlled by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 is overproduced in many human cancers, thereby impairing p53 function. Antagonists of p53-MDM2 interaction can enhance p53 activity and offer a novel approach to cancer therapy. The first potent and selective small-molecule inhibitors of p53-MDM2 binding, the nutlins, provided preclinical proof-of-concept for MDM2 antagonists as therapeutics for patients with tumors expressing wild-type p53. The nutlin family member idasanutlin (RG7388, RO5503781) is an oral small molecule inhibitor of MDM2 currently in clinical testing. Here we describe RO6839921, a pegylated prodrug formulated for intravenous administration. This IV MDM2 antagonist has been developed in order to improve variability in exposure seen with the oral compound, and to allow expansion into indications where patients cannot swallow or absorb the oral idasanutlin. RO6839921 is rapidly metabolized to the active principle (AP) idasanutlin which then binds selectively to the p53 site on the surface of the MDM2 molecule. In vitro testing with the AP shows high affinity with effective displacement of p53 from MDM2, leading to stabilization and accumulation of p53 protein and activation of the p53 pathway. Studies focused on in vivo investigation of activity of the prodrug RO6839921 since esterase cleavage is required to release the AP. The anti-tumor activity of RO6839921 was investigated in several sarcoma xenograft models including highly responsive wild-type (WT) p53, MDM2 overexpressing osteosarcoma models SJSA-1 and MHM. Sustained survival was seen in the WT p53 HT1080 fibrosarcoma model when combined with Doxil. Activity was also seen in the WT p53 MOLM-13 disseminated AML model alone and in combination with cytarabine, in the CRPC model 22rv1, and in the ER+ BCa model MCF-7. In these studies we see an increase in dose commensurate with exposure and activity (prodrug vs oral), less variability, and potentiated activity in combination with relevant therapeutics. Clinical studies with the oral AP (idasanutlin) have shown that p53 may be activated by this novel therapeutic strategy that releases p53 from MDM2 inhibition. In particular, patients with AML exhibit significant clinical activity (ASH 2014). In view of the existing unmet medical need in advanced cancers, and the promising activity seen with idasanutlin, RO6839921 is believed to be a promising agent that may offer new therapeutic options, and is therefore currently in clinical testing in both solid and hematologic malignancies. Citation Format: Brian Higgins, Christian Tovar, Kelli Glen, Aruna Railkar, Zoran Filipovic, Farooq Qureshi, Binh Vu, George Ehrlich, Dan Fishlock, Lin-Chi Chen, Steven Middleton, Gwen Nichols, Kathryn Packman, Lyubomir Vassilev. Preclinical activity of MDM2 antagonist RO6839921, a pegylated prodrug for intravenous administration. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A156.