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

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

PROVIDER: PRJNA779922 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16928915_1.fastq.gz	Fastqsanger.gz
	SRR16928915_2.fastq.gz	Fastqsanger.gz
	SRR16928916_1.fastq.gz	Fastqsanger.gz
	SRR16928916_2.fastq.gz	Fastqsanger.gz
	SRR16928917_1.fastq.gz	Fastqsanger.gz

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

Project description:We report scRNA-seq data showing the effect of palbociclib treatment on medulloblastomas that form in Smo-mutant mice. We generate tumor-bearing mice by breeding hGFAP-Cre and SmoM2 mouse lines to prodce tumor-prone progeny heterozygous for both transgenes (G-Smo mice). We compare tumors from untreated G-Smo mice to tumors from G-Smo ice treated with nanoparticle--delievered palbociclib, using Drop-seq-based scRNA-seq.

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

Project description: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.

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