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 a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.
Highlights
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor among adults and carries a grim prognosis with less than a 5% chance of 5-year survival following standard therapy
Li Fraumeni Patient Was Identified as a Candidate for Comparative Transcriptomics Pipeline
We found that Patient 23 had overexpression of JAK and was a suitable candidate for ruxolitinib treatment (Figure 4A)
Summary
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor among adults and carries a grim prognosis with less than a 5% chance of 5-year survival following standard therapy. A contributing factor to poor patient response is the one-size-fits-all treatment approach to a heterogeneous tumor, which, despite extensive efforts to genetically subtype, is molecularly unique from patient to patient [3]. This suggests a clear need for the development and identification of personalized treatment strategies, especially for the rare forms of GBM, which result from cancer predisposition syndromes. Patients with LFS can serve as an important genetic model to target TP53 mutant tumors
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