CDK 4/6 Inhibitors are Potent Radiosensitizers in Retinoblastoma Protein Positive Meningiomas

Abstract

<h3>Purpose/Objective(s)</h3> 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. <h3>Materials/Methods</h3> Three experiments were performed: <b>#1</b>). 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 ‘<i>Back Translation Method</i>' 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; <b>#2</b>). To compare the effectiveness of the 3 CDK 4/6 inhibitors administered at clinically relevant doses (<b>from</b> <i>#1</i>) for 14 days +/- whole brain radiotherapy (WBRT) (20 Gy/10fr) against orthotopic meningioma CH157 xenografts; <b>#3</b>). To confirm the efficacy of the most potent inhibitor (<b>from #2</b>), +/- 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 <b>(#3</b>). <h3>Results</h3> <b>Experiment 1:</b> The clinically relevant mouse drug doses were 15 mg/kg BID (PBCL), 150 mg/kg QD (RBCL), and 15 mg/kg BID (ABCL). <b>Experiment 2:</b> 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. <b>Experiment 3:</b> 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). <h3>Conclusion</h3> Among the CDK 4/6 inhibitors administered at human clinically relevant doses, <i>Ribociclib</i> 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.