MDM2 inhibitor therapy for TP53 wild-type GBM

Project Summary – Project 2 Disruption of tumor suppressor p53 function is the most common alteration in cancer and results in dysregulation of DNA repair following genotoxic insults. Use of small molecule inhibitors blocking the interaction of p53 with murine double minute 2 (MDM2) prevents MDM2-mediated degradation of p53 and is the most clinically advanced strategy to target this critical DNA damage response pathway. In this project, we introduce the highly potent MDM2 inhibitor BI-907828 as a novel therapeutic approach against glioblastoma (GBM). This best-in-class MDM2 inhibitor is highly potent in vitro in GBM PDXs at single-digit nanomolar concentrations. BI-907828 monotherapy has significant anti-tumor activity against orthotopic GBM PDXs with corresponding robust evidence of on-target pharmacodynamic drug effects – stabilization of p53 and increased p53-mediated transcription of pro-apoptotic genes. Further, combined therapy with BI-907828 and radiation markedly enhances induction of pro-apoptotic genes in both the extrinsic and intrinsic apoptotic pathway, and combined radiation/BI-907828 therapy in orthotopic PDXs results in profound extension of animal survival in two GBM PDXs. This activity in orthotopic PDX models known to have an intact blood brain barrier is especially interesting since BI-907828 has relatively limited distribution into normal brain. In contrast to modulation of mitogenic signaling or many other DNA repair targets, which require sustained, high-level suppression of optimal effects, MDM2 tightly regulates p53 stability in a negative feedback loop. Thus, we hypothesize that even short-term inhibition of MDM2 activity can lead to increased expression of p53 sufficient to activate pro-apoptotic effects of p53. Defining the differences in pharmacologic effect when targeting distinct types of regulatory circuits (e.g., positively cooperative signaling networks vs. negative feedback transcriptional networks) represents a key innovation of the planned project. The specific Aims of the project are: Aim 1: Develop a PK→PD→efficacy model for BI-907828 monotherapy in GBM PDXs Aim 2: Conduct a phase 0 trial to evaluate the distribution and pharmacodynamics of BI-907828 in GBM Aim 3: Determine the tolerability of BI-907828 combined with radiation in patients with newly diagnosed GBM Aim 4: Evaluate combinatorial strategies for BI-907828 with other anticancer therapies for GBM