Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq–guided combination with sapanisertib

Abstract

The therapeutic potential of CDK4/6 inhibitors for brain tumors has been limited by recurrence. To address recurrence, we tested a nanoparticle formulation of CDK4/6 inhibitor palbociclib (POx-Palbo) in mice genetically-engineered to develop SHH-driven medulloblastoma, alone or in combination with specific agents suggested by our analysis. Nanoparticle encapsulation reduced palbociclib toxicity, enabled parenteral administration, improved CNS pharmacokinetics, and extended mouse survival, but recurrence persisted. scRNA-seq identified up-regulation of glutamate transporter Slc1a2 and down-regulation of diverse ribosomal genes in proliferating medulloblastoma cells in POx-Palbo–treated mice, suggesting mTORC1 signaling suppression, subsequently confirmed by decreased 4EBP1 phosphorylation. Combining POx-Palbo with the mTORC1 inhibitor sapanisertib produced mutually enhancing effects and prolonged mouse survival compared to either agent alone, contrasting markedly with other tested drug combinations. Our data show the potential of nanoparticle formulation and scRNA-seq analysis of resistance to improve brain tumor treatment and identify POx-Palbo + Sapanisertib as effective combinatorial therapy for SHH medulloblastoma.

PRC2 disruption in cerebellar progenitors produces cerebellar hypoplasia and aberrant myoid differentiation without blocking medulloblastoma growth

“…We subjected scRNA-seq data from Eed cKO and WT cells to principal component analysis (PCA) and Louvain clustering, as in our prior studies (3, 35, 36), to identify 20 clusters, numbered from 0, most populous, to 19, least populous (Supplementary Fig.1). We then determined cluster-specific gene expression profiles by comparing the expression of each detected gene in cells within the cluster versus all cells outside the cluster (Supplementary Data 1).…”

“…Mouse brains were processed, immunostained, and quantified as previously described (Ocasio et al, 2019a;Malawsky et al, 2021;Lim et al, 2022;Lang et al, 2016). In brief, mice were placed under isoflurane anesthesia and decapitated.…”

“…We subjected scRNA-seq data from Eed cKO and WT cells to principal component analysis (PCA) and Louvain clustering, as in our prior studies (3,35,36), to identify 20 clusters, numbered from 0, most populous, to 19, least populous (Supplementary Fig. 1).…”

The Tumor Microenvironment of Medulloblastoma: An Intricate Multicellular Network with Therapeutic Potential

“…They indicated that chemotherapeutic drug delivery in MB could be improved if it is combined with agents that briefly open the BBB, such as nanoparticles [ 131 ]. Recently, multiple studies have proven the favorable effects of nanoparticle drug delivery for the treatment of both SHH-driven and group 3 MB [ 132 , 133 , 134 , 135 , 136 ]. Lipid–polymer hybrid nanoparticles, which are core–shell nanoparticles, were applied to prolong and increase the efficacy of a therapeutic smoothened targeting siRNA against SHH-MB [ 132 ].…”

“…The combination with microbubble-enhanced low-intensity focused ultrasound promoted the extravasation of the BBB and tumor. Furthermore, organic nanostructured materials such as liposomes [ 133 ] and polymeric micelles [ 134 , 135 , 136 ] have been utilized to improve the delivery of therapeutic agents over the BBB in SHH-MB tumors. Notably, polymeric micelles enhanced the therapeutic potential of vismodegib by reducing the bone toxicity and improving the central nervous system pharmacokinetics [ 135 ].…”