Abstract 3084: BI-907828: A novel, potent MDM2 inhibitor, inhibits GBM brain tumor stem cells in vitro and prolonged survival in orthotopic xenograft mouse models

Abstract

Abstract Glioblastoma (GBM) is characterized by an aggressive clinical course, therapeutic resistance and striking molecular heterogeneity. GBM remains incurable with a median survival of 12-15 months post-surgery even with standard of care chemotherapy and radiation. The tumor suppressor p53 (TP53) is frequently mutated in cancer and along with its downstream effectors is inactivated in more than half of all cancers. The remaining 50% of tumors have TP53 wild-type status. However, TP53 function is frequently attenuated in these cancers by other mechanisms including amplification and overexpression of its key negative regulator MDM2. Inhibition of the protein-protein interaction between p53 and MDM2 is still a novel concept for cancer therapy. MDM2 inhibitors are designed to restore and maintain p53 activity in p53 wild-type tumors. BI-907828, currently in Phase I clinical trials, is a novel and potent MDM2 inhibitor with good oral bioavailability and pharmacokinetic properties. We investigated the efficacy of BI-907828 in p53 wild-type GBM patient-derived brain tumor stem cell (BTSC) lines with different amplification status of MDM2. BI-907828 potently reduced proliferation and viability in BTSC lines with IC50 values in the picomolar range. All BTSC lines, including lines resistant to the standard of care for GBM, temozolomide (TMZ), were sensitive to the MDM2 inhibitor irrespective of the copy number (CN) status of the MDM2 gene. Consistently, induction of cell death by BI-907828 was demonstrated in a BTSC line with an MDM2 gene amplification, as well as in another line with wild-type MDM2 CN status. PK-PD studies in SCID mice, orthotopically xenografted with BTSC lines, demonstrated that a single dose of BI-907828 resulted in strong activation of target genes. Human CDKN1a and GDF15 mRNA levels were significantly increased in brain tumor tissue in both the MDM2-amplified and non-amplified orthotopic models, suggesting that BI-907828 is able to pass the blood-brain-barrier and demonstrates on-target MDM2 inhibition in vivo. Efficacy of BI-907828 was assessed in Kaplan Meier survival studies as monotherapy or in combination with TMZ in two orthotopic BTSC xenograft models with MDM2 amplified or wild-type CN status, respectively and both with p53 wild-type status and promoter methylation of the MGMT gene. Long-term treatment with BI-907828 as monotherapy or in combination with TMZ was well tolerated in both these orthotopic BTSC xenograft models for several months. BI-907828 treatment demonstrated striking improved efficacy over vehicle control animals in both models. There was also significant survival benefit for the combinatorial treatment with TMZ in the MDM2 wild-type CN model over monotherapies alone. BI-907828 thus provides an extremely promising new therapeutic option for patients with primary brain tumors. Citation Format: Hema A. Luchman, Danielle Bozek, Xiaoguang Hao, Dorothea Rudolph, Sophia Blake, Jörg Rinnenthal, Samuel Weiss. BI-907828: A novel, potent MDM2 inhibitor, inhibits GBM brain tumor stem cells in vitro and prolonged survival in orthotopic xenograft mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3084.