Translational validation of personalized treatment strategy based on genetic characteristics of glioblastoma

• Published in: PloS one 2014-08, Vol.9 (8), p.e103327-e103327
• Main Authors: Oh, Young Taek, Cho, Hee Jin, Kim, Jinkuk, Lee, Ji-Hyun, Rho, Kyoohyoung, Seo, Yun-Jee, Choi, Yeon-Sook, Jung, Hye Jin, Song, Hyeon Suk, Kong, Doo-Sik, Seol, Ho Jun, Lee, Jung-Il, Yoon, Yeup, Kim, Sunghoon, Nam, Do-Hyun, Joo, Kyeung Min
• Format: Article
• Language: English
• Subjects: Abnormalities; Adult; Aged; Analysis; Animal models; Animals; Antineoplastic Agents - pharmacology; Biology and Life Sciences; Biomedical research; Brain cancer; Brain Neoplasms - diagnosis; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - mortality; Brain research; Breast cancer; Cancer; Cancer genetics; Cancer therapies; Chi-square test; Classification; Cluster Analysis; Dilution; Disease Models, Animal; Drug development; Drugs; Female; Gene expression; Gene Expression Profiling; Gene Regulatory Networks; Genomes; Genomics; Glioblastoma; Glioblastoma - diagnosis; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - mortality; Glioblastomas; Health aspects; Health sciences; Humans; Laboratory animals; Male; Medical prognosis; Medical research; Medicine; Medicine and Health Sciences; Metastasis; Mice; Middle Aged; Molecular modelling; Molecular Targeted Therapy; Mutation; Neurosurgery; Pancreatic cancer; Patients; Pharmacogenetics; Pharmacology; Pharmacy; Precision Medicine; Prognosis; Research and Analysis Methods; Surgery; Temozolomide; Therapeutic applications; Translational Medical Research; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0103327

Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated.