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Meningiomas are the most common primary brain tumor. Preclinical efficacy of CDK 4/6 inhibitors, routinely used in breast cancer, has been demonstrated against retinoblastoma protein (RB) positive meningiomas. We investigated three CDK 4/6 inhibitors to identify the most potent radiosensitizer as a candidate drug for the next NRG trial. Three experiments were performed: #1). PK experiment to determine the clinically relevant dose (for human trials) of CDK 4/6 inhibitors in six-week-old male athymic nude mice. The ' Back Translation Method ' was used (Spilker et al., Cancer Res 2018). The drug doses given orally for 4 days were: Ribociclib (RBCL) 50 and 150 mg/kg daily, Palbociclib (PBCL) 30mg/kg daily, Abemaciclib (ABCL) 25 and 75 mg/kg daily. Blood samples (25 mice x 4) were collected at 1, 4, 7 and 24 hours and PK analysis was conducted by Pfizer; #2). To compare the effectiveness of the 3 CDK 4/6 inhibitors administered at clinically relevant doses ( from #1) for 14 days +/- whole brain radiotherapy (WBRT) (20 Gy/10fr) against orthotopic meningioma CH157 xenografts; #3). To confirm the efficacy of the most potent inhibitor ( from #2 ), +/- WBRT (10 Gy/5fr) against a second orthotopic meningioma (IOMM-Lee) xenografts. Study End Points (Experiments 2 and 3): Bioluminescence Imaging (BLI) for tumor growth and overall survival. RNA-seq was done to detect differential tumor gene expression (#3). Experiment 1: The clinically relevant mouse drug doses were 15 mg/kg BID (PBCL), 150 mg/kg QD (RBCL), and 15 mg/kg BID (ABCL). Experiment 2: Median overall survival in days was 12, 14, 15, 17, 17, 16, 19, and 26, for Control, PBCL, RBCL, ABCL, RT, RT + ABCL, RT + PBCL and RT + RBCL, respectively. Hazard ratios for death, using RT + RBCL as reference were: 68.68, 7.08, 3.19, and 2.52 for Controls (P = 1.03e-08), RT+ ABCL (P = 5.42e-04), RT+ PBCL (P = 0.02) and RT (P = 0.068), respectively. The log BLI was consistently lower in RT + RBCL. Experiment 3: Median overall survival was 19, 29, 27, and 59 days for Control, RT, RBCL, and RT + RBCL, respectively. Hazard ratios for death using RT + RBCL as reference were: 70.9, 5.21, 4.85 for Controls (P = 1.90e-10), RT (P = 0.001), and RBCL (P = 0.002), respectively. Log BLI was consistently lower in RT + RBCL. RNA-seq showed significant down-regulation of interferon-beta and -gamma response pathways in all treatment arms compared to controls. Treatment-specific changes include: up-regulation of cell-cell adhesion, gliogenesis (RBCL), upregulation of MAPK signaling pathway and neuronal death (RT) and upregulation of mTOR signaling pathway, glycolysis and gluconeogenesis, and negative regulation of cell proliferation (RT+RBCL). Among the CDK 4/6 inhibitors administered at human clinically relevant doses, Ribociclib was the most potent radiosensitizer against meningioma xenografts. The combination of Ribociclib and RT will be considered for the next NRG protocol for high-risk biomarker positive (RB protein) primary and recurrent meningiomas. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Recent autopsy data from patients with glioblastoma (GBM) has demonstrated that pronounced brainstem infiltration is now a common pattern of disease progression near the end of life. The present study evaluated the association of disease proximity to the brainstem on imaging, both at diagnosis and at recurrence, with overall survival (OS).Materials/methods: 140 patients with IDH wild-type GBM treated definitively with resection and adjuvant chemoradiation at a single institution from 2013-2019 were retrospectively analyzed. Disease proximity to brainstem was calculated from measurements made on T1 post-contrast MRI brain obtained at diagnosis postoperatively and at recurrence. Tumor volume was approximated by the resection cavity plus adjacent extrinsic enhancement, measured during target delineation at time of treatment delivery. The Kaplan-Meier method was used to estimate OS, and multivariable analysis was performed using the Cox proportional hazards model. Logistic regression was used to assess the effect of tumor volume on brainstem involvement, and the relationship between tumor volume and proximity to brainstem was assessed by the Spearman correlation.Results: Median distance of disease to brainstem was 22.4 mm (range 0-54) at diagnosis, with 2.1% (n = 3) having brainstem involvement. At 56-month median follow-up, 87% of patients had recurrence; 2-year OS was 38.6%. Median distance of disease to brainstem was 20.8 mm (range 0-63) at recurrence, with 5.7% (n = 8) having brainstem involvement at recurrence. Controlling for resection status, MGMT methylation, and Karnofsky performance status, there was no noted association of brainstem invasion (P = .60) or proximity at diagnosis (P = .14) with OS. However, at recurrence, distance from the brainstem was significantly associated with improved OS when measured continuously (HR: .97, 95% CI: .95-.99, P = 0.001) and when compared by group (20-40 mm vs. ≤20 mm: HR .59, 95% CI: .35-.99, P = 0.05; > 40 mm vs. ≤20 mm: HR .16, 95% CI: 0.05-.55, P = 0.003). While volume of tumor at diagnosis was not found to be independently associated with brainstem involvement (P = .99) or OS (P = .90) at recurrence, tumor volume at diagnosis was found to be significantly associated with disease proximity to brainstem at the time of recurrence (P = 0.037), with larger volume disease more likely to recur close to the brainstem.Conclusion: GBM proximity to the brainstem at diagnosis was not found to be prognostic, whereas disease proximity to the brainstem at recurrence was associated with worse OS. Tumor volume at diagnosis was found to be associated with disease proximity at recurrence, with higher volume disease at diagnosis associated with greater proximity to the brainstem at recurrence. These findings may have ramifications for upfront and salvage radiation treatment design.Author Disclosure: A. Bajaj: None. E.T. Benishay: None. I.B. Helenowski: None. R. Savoor: None. M.R. Drumm: None. N. Rammohan: None. S. Sachdev: None. C.M. Horbinski: None. T. Kruser: Employee; Northwestern Memorial Hospital. Honoraria; Elsevier, OncLive. Speaker's Bureau; AstraZeneca. Advisory Board; AstraZeneca. [ABSTRACT FROM AUTHOR]