Data from Preclinical Efficacy of the MDM2 Inhibitor RG7112 in <i>MDM2</i>-Amplified and <i>TP53</i> Wild-type Glioblastomas

Abstract

<div>Abstract<p><b>Purpose:</b> p53 pathway alterations are key molecular events in glioblastoma (GBM). MDM2 inhibitors increase expression and stability of p53 and are presumed to be most efficacious in patients with <i>TP53</i> wild-type and <i>MDM2</i>-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM.</p><p><b>Experimental Design:</b> We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCL), each genetically characterized according to their P53 pathway status. We then performed a pharmacokinetic (PK) profiling of RG7112 distribution in mice and evaluated the therapeutic activity of RG7112 in orthotopic and subcutaneous GBM models.</p><p><b>Results:</b> <i>MDM2</i>-amplified PDCLs were 44 times more sensitive than <i>TP53</i>-mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC<sub>50</sub> of 0.52 μmol/L vs. 21.9 μmol/L). <i>MDM4</i>-amplified PDCLs were highly sensitive but showed intermediate response (avg. IC<sub>50</sub> of 1.2 μmol/L), whereas response was heterogeneous in <i>TP53</i> wild-type PDCLs with normal MDM2/4 levels (avg. IC<sub>50</sub> of 7.7 μmol/L). In <i>MDM2</i>-amplified lines, RG7112 restored p53 activity inducing robust p21 expression and apoptosis. PK profiling of RG7112-treated PDCL intracranial xenografts demonstrated that the compound significantly crosses the blood–brain and the blood–tumor barriers. Most importantly, treatment of <i>MDM2</i>-amplified/<i>TP53</i> wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival.</p><p><b>Conclusions:</b> These data strongly support development of MDM2 inhibitors for clinical testing in <i>MDM2</i>-amplified GBM patients. Moreover, significant efficacy in a subset of non–<i>MDM2</i>-amplified models suggests that additional markers of response to MDM2 inhibitors must be identified. <i>Clin Cancer Res; 22(5); 1185–96. ©2015 AACR</i>.</p></div>