Transcriptomics

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Functional precision medicine pipeline combines comparative transcriptomics and tumor organoid modeling to identify be-spoke treatment strategies for glioblastoma


ABSTRACT: Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer occurring in 30-50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used novel comparative transcriptomics analysis to identify genes that are uniquely overexpressed in a LFS GBM patient relative to a cancer compen-dium of 12,747 tumor RNA sequencing datasets including 200 GBMs. We then used ex vivo pa-tient derived organoid (PDO) viability assays with 4 patient derived cell lines to test efficacy of our identified target. Our comparative transcriptomics bioinformatics pipeline identified that STAT1 and STAT2 were significantly overexpressed in our patient indicating ruxolitinib, a Janus kinase 1 and 2 inhibitor, as a potential therapy. In our institutional high-grade glioma cohort of 45 patients, the LFS patient had the highest level of STAT1 and STAT2 expression. STAT1 and STAT2 expression levels in 4 cell lines derived from patients (including the LFS patient) corre-lated with levels identified in the respective parent tumors. Using 2D and 3D assays from pa-tient derived cells, our LFS patient of interest was among the most sensitive to ruxolitinib in comparison to patients with lower STAT1 and STAT2 expression levels. Additionally a sphe-roid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188739 | GEO | 2021/12/02

REPOSITORIES: GEO

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