Abstract
Malignant rhabdoid tumors (MRTs) represent one of the most aggressive childhood malignancies. No effective treatment options are available, and prognosis is, therefore, dismal. Previous studies have demonstrated that tumor organoids capture the heterogeneity of patient tumors and can be used to predict patient response to therapy. Here, we perform drug screening on patient-derived normal and tumor organoids to identify MRT-specific therapeutic vulnerabilities. We identify neddylation inhibitor MLN4924 as a potential therapeutic agent. Mechanistically, we find increased neddylation in MRT organoids and tissues and show that MLN4924 induces a cytotoxic response via upregulation of the unfolded protein response. Lastly, we demonstrate invivo efficacy in an MRT PDX mouse model, in which single-agent MLN4924 treatment significantly extends survival. Our study demonstrates that organoids can be used to find drugs selectively targeting tumor cells while leaving healthy cells unharmed and proposes neddylation inhibition as a therapeutic strategy in MRT.
Highlights
Malignant rhabdoid tumors (MRTs) are aggressive childhood tumors that occur in infants and young children (Weeks et al, 1989)
Extensive analyses revealed that the organoids have retained crucial characteristics of the parental tissue (Figures S1A–S1E), as we previously described for our MRTs of the kidney models (Calandrini et al, 2020; Chun et al, 2019)
We screened a total of six MRT organoid lines derived from five patients with MRTs, including three primary tumors, one metastasis, and one case of patientmatching primary and metastatic tissue (Calandrini et al, 2020)
Summary
Malignant rhabdoid tumors (MRTs) are aggressive childhood tumors that occur in infants and young children (Weeks et al, 1989). They can arise in the brain (atypical teratoid rhabdoid tumor [ATRT]) as well as extracranially (kidney and soft tissues), where they are collectively called MRTs. MRTs are uniquely characterized by one common genetic driver event, bi-allelic loss of SMARCB1 (95%) or SMARCA4 (5%), key members of the SWI/SNF chromatin-remodeling complex (Biegel et al, 1999; Versteege et al, 1998). The prognosis remains dismal, with an overall survival of only 25% (Reinhard et al, 2008). Survivors suffer from side effects of the intense treatment regimen. MRTs, remain one of the big challenges in childhood cancer, and the identification of less-toxic therapeutic strategies is urgently needed
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