Abstract
Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.
Highlights
Candidate therapeutics for personalized treatment in rare tumors are difficult to test in clinical trials because of intertumor differences and the limited number of patients representing specific genetic profiles
Glioma organoids and patient-derived orthotopic xenografts (PDOX) can be generated across diverse clinical high‐grade glioma specimens
We present a living tumor biobank that encompasses the clinical diversity of high-grade diffuse gliomas
Summary
Candidate therapeutics for personalized treatment in rare tumors are difficult to test in clinical trials because of intertumor differences and the limited number of patients representing specific genetic profiles. GBM, characterized as Isocitrate dehydrogenase wild type (IDHwt), encompasses tumors with varying genetic backgrounds that affect distinct signaling networks [11, 14]. They can be classified into molecular subtypes with differing expression signatures [107, 112], display variable DNA ploidy [92] and have different DNA methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter. The latter has been shown to predict the response to temozolomide (TMZ) [48], the standard-of-care chemotherapeutic agent approved for GBM [94]. All targeted treatment attempts in gliomas, e.g., targeting EGFR [41], have failed in clinical trials and effective treatment strategies are urgently needed
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