RESUMEN
Outcomes for adult patients with a high-grade glioma continue to be dismal and new treatment paradigms are urgently needed. To optimize the opportunity for discovery, we performed a phase 0/1 dose-escalation clinical trial that investigated tumor pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics following combined ribociclib (CDK4/6 inhibitor) and everolimus (mTOR inhibitor) treatment in recurrent high-grade glioma. Patients with a recurrent high-grade glioma (n = 24) harboring 1) CDKN2A / B deletion or CDK4 / 6 amplification, 2) PTEN loss or PIK3CA mutations, and 3) wild-type retinoblastoma protein (Rb) were enrolled. Patients received neoadjuvant ribociclib and everolimus treatment and no dose-limiting toxicities were observed. The median unbound ribociclib concentrations in Gadolinium non-enhancing tumor regions were 170 nM (range, 65 - 1770 nM) and 634 nM (range, 68 - 2345 nM) in patients receiving 5 days treatment at the daily dose of 400 and 600 mg, respectively. Unbound everolimus concentrations were below the limit of detection (< 0.1 nM) in both enhancing and non-enhancing tumor regions at all dose levels. We identified a significant decrease in MIB1 positive cells suggesting ribociclib-associated cell cycle inhibition. Single nuclei RNAseq (snRNA) based comparisons of 17 IDH-wild-type on-trial recurrences to 31 IDH-wild-type standard of care treated recurrences data demonstrated a significantly lower fraction of cycling and neural progenitor-like (NPC-like) malignant cell populations. We validated the CDK4/6 inhibitor-directed malignant cell state shifts using three patient-derived cell lines. The presented clinical trial highlights the value of integrating pharmacokinetics, pharmacodynamics, and single nucleus transcriptomics to assess treatment effects in phase 0/1 surgical tissues, including malignant cell state shifts. ClinicalTrials.gov identifier: NCT03834740 .
RESUMEN
Cerebrospinal fluid (CSF) analysis is underutilized in patients with glioblastoma (GBM), partly due to a lack of studies demonstrating the clinical utility of CSF biomarkers. While some studies show the utility of CSF cell-free DNA analysis, studies analyzing CSF metabolites in patients with glioblastoma are limited. Diffuse gliomas have altered cellular metabolism. For example, mutations in isocitrate dehydrogenase enzymes (e.g., IDH1 and IDH2) are common in diffuse gliomas and lead to increased levels of D-2-hydroxyglutarate in CSF. However, there is a poor understanding of changes CSF metabolites in GBM patients. In this study, we performed targeted metabolomic analysis of CSF from n = 31 patients with GBM and n = 13 individuals with non-neoplastic conditions (controls), by mass spectrometry. Hierarchical clustering and sparse partial least square-discriminant analysis (sPLS-DA) revealed differences in CSF metabolites between GBM and control CSF, including metabolites associated with fatty acid oxidation and the gut microbiome (i.e., carnitine, 2-methylbutyrylcarnitine, shikimate, aminobutanal, uridine, N-acetylputrescine, and farnesyl diphosphate). In addition, we identified differences in CSF metabolites in GBM patients based on the presence/absence of TP53 or PTEN mutations, consistent with the idea that different mutations have different effects on tumor metabolism. In summary, our results increase the understanding of CSF metabolites in patients with diffuse gliomas and highlight several metabolites that could be informative biomarkers in patients with GBM.