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A novel in vivo model of Glioblastoma radiation resistance identifies long non-coding RNAs and targetable kinases

ABSTRACT: A novel in vivo model of Glioblastoma radiation resistance identifies long non-coding RNAs and targetable kinases

PROVIDER: PRJNA849764 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19668127_1.fastq.gz	Fastqsanger.gz
	SRR19668127_2.fastq.gz	Fastqsanger.gz
	SRR19668128_1.fastq.gz	Fastqsanger.gz
	SRR19668128_2.fastq.gz	Fastqsanger.gz
	SRR19668129_1.fastq.gz	Fastqsanger.gz

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A novel in vivo model of Glioblastoma radiation resistance identifies long non-coding RNAs and targetable kinases

Project description:Glioblastomas (GBM) are the most common primary CNS tumor. GBMs often recur as highly aggressive, intractable, therapy resistant tumors. Key molecular regulators of acquired radiation resistance in recurrent GBM are largely unknown with a dearth of accurate pre-clinical models. To address this, we generated eight GBM patient-derived xenograft (PDX) models of acquired radiation-therapy selected (RTS) resistance compared with same-patient, treatment naïve (RTU) PDX. A novel bioinformatics pipeline analyzed phenotypic, transcriptomic and kinomic alterations, identifying long non-coding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair (DDR) pathways in our RTS models. Multiple molecular routes to acquired radiation-resistance were revealed in our models including PDX-specific kinases that we validated with targeted small molecule inhibitors (SMIs). We identified 184, mostly novel, lncRNAs differentially regulated between RTU and RTS PDX. Several of these lncRNAs were associated with transcriptional changes in DDR, cell cycle progression, stemness, and chromatin remodeling pathways. This study identifies lncRNAs as potential key regulators in recurrent GBM and therapy resistance. We also demonstrate that SMIs aimed at lncRNA-related signaling pathways may represent a novel therapeutic approach for recurrent GBM tumors.

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Project description:Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown, with a dearth of accurate preclinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy-selected (RTS) resistance compared with same-patient, treatment-naive (radiation-sensitive, unselected; RTU) PDXs. These likely unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy. Indeed, while whole-exome sequencing showed retention of major genomic alterations in the RTS lines, we did detect a chromosome 12q14 amplification that was associated with clinical GBM recurrence in 2 RTS models. A potentially novel bioinformatics pipeline was applied to analyze phenotypic, transcriptomic, and kinomic alterations, which identified long noncoding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair pathways in our RTS models, which correlated with several lncRNAs. Global kinomic profiling separated RTU and RTS models, but pairwise analyses indicated that there are multiple molecular routes to acquired radiation resistance. RTS model-specific kinases were identified and targeted with clinically relevant small molecule inhibitors. This cohort of in vivo RTS patient-derived models will enable future preclinical therapeutic testing to help overcome the treatment resistance seen in patients with GBM.

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Dopamine Receptor Antagonists and Radiation Create a Metabolic Vulnerability in Mouse Models of Glioblastoma

Project description:Glioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. Using patient-derived glioblastoma lines and mouse models of glioblastoma we tested the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism was investigated using RNA-Sequencing. Treatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals. Our results indicate promising therapeutic efficacy with the triple combination of quetiapine, atorvastatin and radiation treatment against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

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Menin is a Targetable Epigenetic Regulator in Glioblastoma (RNA-Seq)

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