Systematic design of combination therapy by targeting master regulators of coexisting diffuse midline glioma cell states

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.

Authors / organisation

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.

Venue

Nature Genetics

Date

2026-04-22

Type

paper

Year

2026

DOI

10.1038/s41588-026-02550-w

PMID

42020604

Verification

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

DMGDrug responsePerturbationTherapyPreclinicalGene regulatory network

Open in the searchable library → · JSON