Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas

Abstract

Rationale 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 TP53 wild-type and MDM2-amplified cancers. However, this biomarker hypothesis has not been tested in patients or patient-derived models for GBM. Methods We performed a preclinical evaluation of RG7112 MDM2 inhibitor, across a panel of 36 patient-derived GBM cell lines (PDCLs), 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. Results MDM2-amplified PDCLs were 44 times more sensitive than TP53 mutated lines that showed complete resistance at therapeutically attainable concentrations (avg. IC50 of 0.52 μM vs 21.9 μM). MDM4 amplified PDCLs were highly sensitive but showed intermediate response (avg. IC50 of 1.2 μM), whereas response was heterogeneous in TP53 wild-type PDCLs with normal MDM2/4 levels (avg. IC50 of 7.7 μM). In MDM2-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 MDM2-amplified/TP53 wild-type PDCL-derived model (subcutaneous and orthotopic) reduced tumor growth, was cytotoxic, and significantly increased survival. Conclusion These data strongly support development of MDM2 inhibitors for clinical testing in MDM2-amplified GBM patients. Moreover, significant efficacy in a subset of non-MDM2 amplified models suggests that additional markers of response to MDM2 inhibitors must be identified.

Targeting Resistance against the MDM2 Inhibitor RG7388 in Glioblastoma Cells by the MEK Inhibitor Trametinib

“…Primary and acquired resistances are a big challenge and limitation for the effective clinical use of targeted therapies. Although primary resistance mechanisms are widely studied for MDM2 inhibitors in different tumor entities (7,17,18,40), acquired resistance mechanisms are still not fully understood and were not in the focus in neuro-oncology so far.…”

“…1). Overexpression (OE) of MDM2, the key negative regulator of p53, impairs p53 wild-type function and deregulates the MDM2-p53 feedback loop, which results in an accelerated tumor growth in a variety of human tumors, including sarcoma, leukemia, breast cancer, melanoma, and glioblastoma (2)(3)(4)(5)(6)(7). Targeting MDM2 evolved as a promising treatment approach to reactivate the p53 pathway (8) leading to cell-cycle arrest, increased apoptosis, and decreased tumor growth in human tumor xenografts in nude mice (9,10).…”

“…With regards to MDM2 inhibitors, several preclinical studies showed that MDM2 inhibitors reduced tumor growth in p53 wild-type tumors, whereas tumors harboring p53 mutations were primary resistant against the treatment (17)(18)(19). Furthermore, MDM2 amplification in p53 wild-type tumors increased sensitivity to MDM2 inhibitory treatment strategies highlighting MDM2 amplification and p53 wild-type status as potential biomarkers for patient selection (7,20). Acquired resistance mechanisms are still not understood, especially in glioblastoma.…”

Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist

“…The MDM2 gene is amplified in approximately 7%–13% of GBM tumors, and Verreault et al demonstrated that GBM tumors with MDM2 amplification are highly responsive to MDM2 inhibition. 46 However, MDM2 protein is elevated in 45%–75% of GBM biopsy samples, indicating that additional mechanisms can regulate MDM2 expression. 29 MDM2 is an E3 ubiquitin ligase that targets p53 for proteasomal-mediated degradation, blocks the transactivation domain of p53, and is responsible for the export of p53 from the nucleus.…”

“…2,21,22,34,35,45 Although it has been shown that nutlin3a and other MDM2 PPI inhibitors have single-agent activity in inhibiting the growth of a variety of tumor types including GBM, 2,13,14,17,21,22,35,40,44–46 information on dosing regimens that build upon front-line chemotherapy for GBM is lacking. 19,21,22,34,43,45 …”