Therapeutic insights for the aggressive subset of high-grade gliomas (HGG) driven by chromosome 1q32 MDM4-containing amplicon and unmethylated MGMT.
Authors: El-Deiry Wafik S. , Horowitch Brooke , Lou Emil , Subbiah Vivek , Carneiro Benedito A. , Safran Howard , Gokaslan Ziya L. , Sobol Robert W. , Mani Sendurai A. , Lawler Sean E. , Chen Clark C , Wong Eric T. , Kurzrock Razelle , Xiu Joanne , Elliott Andrew , Capelletti Marzia , Ressler Steven , Vanderwalde Ari M. , Nabhan Chadi , Spetzler David 
Published: June 2024

2080 Background: MDM4/MDMX amplification ( MDM4 amp) is associated with poor outcomes, including after immune checkpoint blockade therapy, in multiple tumor types (El-Deiry et al., ASCO, 2022). Glioblastoma (GBM) displays the highest rate of MDM4 amp (9.63%) among all tumor types (Arnoff and El-Deiry, 2022). MDM4 located on chromosome 1q32 can be amplified separately from contactin 2 ( CNTN2) although they can be co-amplified among 17 genes with MDM4 as main amplification target (Riemenschneider et al., 2003). There are no FDA-approved drugs targeting MDMX although there are preclinical compounds such as XI-006 (NSC208895) that can reduce cell migration (George et al., AACR, 2023; De La Cruz, AACR, 2023). We recently uncovered immune-stimulatory effects of temozolomide (TMZ) within hours of drug exposure, prior to cell division and mutation accumulation in microsatellite stable colorectal cancer and HGG (Gonzalez et al., 2023). Here we explored MDM4 amp, co-expressed genes, MGMT, clinical outcomes and response to TMZ. Methods: HGG tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing on DNA and RNA (NGS) were analyzed. MDM4 amp was determined with a cutoff of >/= 4.0 copies. MGMT promoter methylation (me) was tested by pyrosequencing. Patient outcome was obtained from insurance claims data and calculated from start of TMZ (tmzOS) or tissue collection to last contact (rwOS). Cox proportional hazards model, X2/Fisher-Exact was used and p values were adjusted for multiple correction (q value) when appropriate. Results: In a large cohort of 3856 HGG wild-type for IDH1/2, H3F3A and TP53, 300 (8.4%) had MDM4 amp and showed a shorter OS compared to MDM4-not amplified tumors (median rwOS: 14.9 vs 17.3 mo, HR: 1.286; 95% CI: 1.12-1.48, p<0.001). The effect is significant after accounting for age and gender (adjusted p=0.016). MDM4 amp was associated with increased PIK3C2B (fold change: 6.7) and PPP1R15B (FC: 7.9, both q<0.01) expression among other candidates for co-targeting present on Chr 1q32.1; while no significant difference was seen with MGMT-me (p=0.3). Among patients with unmethylated MGMT treated with TMZ (N=1066), MDM4 amp (N=101) was associated with shorter tmzOS (14.3m vs. 15.9m, HR: 1.27, 1.01-1.59, p=0.038) while a trend was seen in the 926 methylated patients (MDM4 Amp: 69, not amplified: 857; tmzOS: 22 m vs. 27.7m, HR: 1.33; 0.95-1.85), p=0.092.). Conclusions: MDM4 amp is negatively associated with clinical outcomes in TP53-WT HGG. The MDM4amplicon on Chr 1q32.1 has associated targets such as PIK3C2B and phosphatase PPP1R15B that may be suitable for therapeutic targeting in a subset of aggressive HGG’s with MDM4 amp. The Chr 1q32 amplicon contains therapeutic targets known to attenuate immune responses and thus their targeting may be combined with various treatments including immunotherapy, targeted therapies, chemotherapy or vaccines.