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• W4362524922 abstract "Abstract Background: The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients. Furthermore, single nuclei RNA sequencing (snRNAseq) provides further insight on the transcriptomic and cell state change in all patients enrolled in the Phase 0 trial. Methods: Eligible patients had recurrent HGG with (1) RB+, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of ribociclib (400mg QD) plus everolimus (2.5mg QD) and underwent tumor resection at 2, 8 or 24 hours following the last dose. Six dose-escalation cohorts (n=3 each) reached a dose-level of ribociclib (600mg QD) plus everolimus (70mg QW). Tumor tissue, CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration &gt; 5-fold biochemical IC50) and a PD ‘trigger’ (&gt;30% decrease in both pRB and pS6) in Gd-nonenhancing tissue were set to qualify patients for expansion. Single nuclei cell analysis was performed on 21 fresh frozen surgical tumor samples to capture transcriptional and cell state changes. Results: 24 patients with WHO Grade III (n=2) and Grade IV (n=22) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM whereas no unbound everolimus concentrations were detected. Across all dose-levels, 57% (13/23) and 43% (10/23) of tumors demonstrated RB and S6 phosphorylation decrease, respectively. snRNAseq analysis revealed significant downregulation of mTOR signaling only in endothelial cells at higher dose levels of everolimus. Amongst the tumor cells, the neural progenitor-like cell state was decreased whereas oligodendrocyte progenitor-like cell state was increased compared to standard-of-care cohort, suggesting a possible inhibition of CDK4-driven neural progenitor-like cell state. Conclusion: In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor. Everolimus exhibits limited penetration into human glioma tissue. Phase 0 surgical tumor tissue is shown to be great resource for identifying pharmacodynamic treatment effect at the single nuclei level. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients. Citation Format: Nader Sanai, An-Chi Tien, Kevin Johnson, Jun Jiang, Yu-Wei Chang, Chelsea Montgomery, Anita DeSantis, Yoko Fujita, Seongho Kim, Jing Li, Roel Verhaak, Shwetal Mehta. Single nuclei RNAseq analysis of recurrent high-grade glioma tumors from patients in the phase 0/1 ‘trigger’ trial of ribociclib plus everolimus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3404." @default.
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• W4362524922 date "2023-04-04" @default.
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• W4362524922 title "Abstract 3404: Single nuclei RNAseq analysis of recurrent high-grade glioma tumors from patients in the phase 0/1 ‘trigger’ trial of ribociclib plus everolimus" @default.
• W4362524922 doi "https://doi.org/10.1158/1538-7445.am2023-3404" @default.
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