{"scope":{"layer":"brain_tumor","tissue_scope":"brain_tumor","species":"unknown","system":"unknown","evidence_level":"peer_reviewed","importance":"","importance_reason":""},"id":"VC0183","type":"paper","title":"Systematic design of combination therapy by targeting master regulators of coexisting diffuse midline glioma cell states","authors_or_org":"Calvo Fernández E, Tomassoni L, Zhang X, Wang J, Obradovic A, Laise P, Griffin AT, Vlahos L, Minns HE, Morales DV, Simmons C, Gallitto M, Wei HJ, Martins TJ, Becker PS, Crawford JR, Tzaridis T, Wechsler-Reya RJ, Garvin J, Gartrell RD, Szalontay L, Zacharoulis S, Wu CC, Zhang Z, Califano A, Pavisic J.","date":"2026-04-22","year":"2026","venue":"Nature Genetics","url":"https://doi.org/10.1038/s41588-026-02550-w","doi":"10.1038/s41588-026-02550-w","pmid":"42020604","brain_tumor_focus":"yes","tags":["dmg","drug-response","perturbation","therapy","preclinical","grn"],"tag_slugs":["dmg","drug-response","perturbation","therapy","preclinical","grn"],"tag_labels":["DMG","Drug response","Perturbation","Therapy","Preclinical","Gene regulatory network"],"tag_labels_zh":["弥漫性中线胶质瘤","药物反应","扰动","治疗","临床前","基因调控网络"],"unmapped_tags":[],"one_line_summary_en":"Calvo Fernández et al. (Califano and Pavisic groups; Nature Genetics 58:1112–1125, 2026) describe a network-based framework to design combination therapies that target complementary coexisting tumor cell states, applied to diffuse midline glioma (DMG). They identify master regulator protein dependencies in seven coexisting cell states (confirmed by pooled CRISPR–Cas9 assays) and use perturbational transcriptional profiles of 372 clinically relevant drugs to prioritize candidates predicted to invert state-specific master regulator activity. State-selective drug sensitivity was validated in vivo for 8 of 9 drugs (including avapritinib, ruxolitinib and larotrectinib); in these preclinical experiments, avapritinib plus ruxolitinib extended median survival nearly threefold versus vehicle and 1.5-fold versus avapritinib alone. No clinical data are reported. Declared interests: A.C. is a founder and equity holder of DarwinHealth, which licenses some of the algorithms used.","one_line_summary_zh":"Calvo Fernández 等（Califano 与 Pavisic 团队；Nature Genetics 58:1112–1125，2026）提出一种基于调控网络的联合疗法设计框架，针对弥漫性中线胶质瘤（DMG）中互补共存的肿瘤细胞状态。研究在 7 种共存细胞状态中识别出主调控蛋白依赖（经混池 CRISPR–Cas9 实验确认），并利用 372 种临床相关药物的扰动转录谱，筛选预测可逆转状态特异主调控活性的候选药物。8/9 种药物（包括阿伐替尼、芦可替尼、拉罗替尼）在体内实验中验证了状态选择性敏感性；在这些临床前实验中，阿伐替尼联合芦可替尼使中位生存期较溶媒对照延长近 3 倍、较阿伐替尼单药延长 1.5 倍。文中未报告临床数据。利益声明：A.C. 为 DarwinHealth 创始人及股东，该公司获授权使用文中部分算法。","verified":"yes","verification_source":"PubMed E-utilities PMID 42020604 (title, 26 authors, Nat Genet 58(5):1112-1125, epub 2026-04-22, abstract, competing-interests statement) + Crossref (journal-article, published online 2026-04-22, CC BY-NC-ND 4.0) fetched 2026-10-20; full text not read","page_url":"https://gliostate.com/library/VC0183/","api_url":"https://gliostate.com/api/items/VC0183.json","sameAs":["https://doi.org/10.1038/s41588-026-02550-w","https://pubmed.ncbi.nlm.nih.gov/42020604/"],"is_preprint":false,"facets":{"type":"https://gliostate.com/library/type/paper/","year":"https://gliostate.com/library/year/2026/","tags":["https://gliostate.com/library/tag/dmg/","https://gliostate.com/library/tag/drug-response/","https://gliostate.com/library/tag/perturbation/","https://gliostate.com/library/tag/therapy/","https://gliostate.com/library/tag/preclinical/","https://gliostate.com/library/tag/grn/"]},"cited_by":[],"related":[{"id":"VC0181","title":"AI Reveals Cancer Drug Combinations","shared_tags":["dmg","drug-response","preclinical"],"page_url":"https://gliostate.com/library/VC0181/","api_url":"https://gliostate.com/api/items/VC0181.json"},{"id":"VC0129","title":"DELPHAI, AI Agent for Predicting Drug Response and Resistance","shared_tags":["therapy","perturbation","drug-response"],"page_url":"https://gliostate.com/library/VC0129/","api_url":"https://gliostate.com/api/items/VC0129.json"},{"id":"VC0126","title":"Keystone: AI and Gene Regulation Across Scales","shared_tags":["grn"],"page_url":"https://gliostate.com/library/VC0126/","api_url":"https://gliostate.com/api/items/VC0126.json"},{"id":"VC0072","title":"A method for in silico exploration of potential glioblastoma multiforme attractors using single-cell RNA sequencing.","shared_tags":["grn"],"page_url":"https://gliostate.com/library/VC0072/","api_url":"https://gliostate.com/api/items/VC0072.json"},{"id":"VC0029","title":"GeneCompass: deciphering universal gene regulatory mechanisms with a knowledge-informed cross-species foundation model.","shared_tags":["grn"],"page_url":"https://gliostate.com/library/VC0029/","api_url":"https://gliostate.com/api/items/VC0029.json"},{"id":"VC0176","title":"A multimodal precision oncology platform integrating genomics, single-cell transcriptomics, and functional drug screening expands therapeutic options in pediatric brain tumors","shared_tags":["drug-response","therapy"],"page_url":"https://gliostate.com/library/VC0176/","api_url":"https://gliostate.com/api/items/VC0176.json"}]}