Dipg-14. Evaluating Therapeutic Vulnerabilities in Dipg Tumors Using High-throughput Screening
Year: 2017
Type: conference-abstract
Abstract: INTRODUCTION: Pediatric high-grade gliomas including Diffuse Intrinsic Pontine Gliomas (DIPGs) are among the most lethal cancers known with no effective cure. Recently, somatic mutations in the H3F3A or HIST1H3B genes have been detected in the majority of midline high-grade pediatric glioma cases which leads to an amino acid change at lysine 27 of H3 to methionine. In an effort to identify drugs for rapid clinical translation, we performed a rigorous high-throughput in vitro drug screen of FDA approved chemotherapeutics and epigenetic regulators. METHODS: Over 200 drugs were tested including FDA approved cancer drugs and a comprehensive library of epigenetic regulators in 6 H3K27M tumors lines and 3 wild type (WT) cell lines using a HTS platform. RESULTS: We identified several major classes of drugs that potently reduce cell viability of DIPG tumors with the H3K27M mutation. Based on these results we uncovered a major signaling pathway that has not been previously reported as a therapeutic target for DIPG. We found proteins in this pathway that were overexpressed in H3K27M tumors compared to WT tumors and normal brain. Furthermore, depletion or inhibition of this pathway selectively inhibit the proliferation of H3K27M mutant DIPG cells, decreases cell colony formation, increases apoptosis compared to WT expressing tumors and restores H3K27 trimethylation patterns. These findings were validated in orthotopic xenografts. CONCLUSION: Malignant gliomas including DIPG, are one of the most aggressive primary malignant brain tumors with no effective therapies at this time. Using a HTS we identified a class of drugs that utilize a specific signaling pathway that is critical for H3K27M tumors. These studies pave the way for developing molecularly targeted therapies as our understanding how these mutations lead to tumorigenesis unfold.
Source: Neuro-Oncology
Authors: Desmond Brown, David Daniels, Liang Zhang
Institution: Mayo Clinic
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2618891167