{"doi":"10.3389/fmed.2023.1254955","title":"Druggable genomic landscapes of high-grade gliomas","abstract":"Background Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging. Methods Using glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug’s clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50). Results Among 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC 50 in GBM cell lines among drugs with clinical efficacy. The drugs’ half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively). Conclusion While multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.","journal":"Frontiers in Medicine","year":2023,"id":343706,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9179,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1082167,"name":"Maria Fatteh","orcid":null,"position":1,"is_corresponding":false},{"id":752154,"name":"David Kamson","orcid":"0000-0002-0473-658X","position":2,"is_corresponding":false},{"id":299298,"name":"Archana Balan","orcid":"0000-0003-1283-577X","position":3,"is_corresponding":false},{"id":663398,"name":"Michael Chang","orcid":"0000-0003-4719-0262","position":4,"is_corresponding":false},{"id":1081736,"name":"Jessica J. Tao","orcid":"0000-0002-6532-4466","position":5,"is_corresponding":false},{"id":80025,"name":"Jaishri O. Blakeley","orcid":"0000-0002-1049-0993","position":6,"is_corresponding":false},{"id":1082168,"name":"The Johns Hopkins Molecular Tumor Board Investigators","orcid":null,"position":7,"is_corresponding":false},{"id":240644,"name":"Jenna VanLiere Canzoniero","orcid":"0000-0003-1084-6918","position":8,"is_corresponding":false},{"id":273502,"name":"Stuart A. Grossman","orcid":"0000-0002-3726-7679","position":9,"is_corresponding":false},{"id":615684,"name":"Kristen A. Marrone","orcid":"0000-0001-5319-824X","position":10,"is_corresponding":false},{"id":463567,"name":"Karisa C. 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