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ATRT-02. THE AURORA KINASE A (AURKA) INHIBITOR ALISERTIB ACTS SYNERGISTICALLY WITH A POLO-LIKE KINASE 4 (PLK4) INHIBITOR TO TARGET ATYPICAL TERATOID / RHABDOID TUMOR (AT/RT) CELLS

ABSTRACT: Abstract BACKGROUND Previously, we observed that CRISPR/Cas9-induced mutations in the PLK4 gene, a critical regulator of centriole duplication, significantly impaired proliferation and survival of AT/RT cells. We established that PLK4 is overexpressed in AT/RT and inhibiting PLK4 resulted in impaired proliferation, survival, migration and invasion. It also induced polyploidy increasing AT/RT susceptibility to DNA-damaging drugs. The inhibition of AURKA, also overexpressed in AT/RT by alisertib, is currently in phase II clinical trial for the treatment of rhabdoid tumors (RT) (NCT02114229). We hypothesized that associating alisertib with a PLK4 inhibitor (PLK4i) would improve the efficacy of each drug. METHODS We tested association of alisertib with the PLK4i CFI-400945 in three RT cell lines (MON, BT-12 and BT-16). Multiple concentrations for each inhibitor alone and in combination were tested. PrestoBlue viability and MTT proliferation assays were performed. RESULTS Median effect plots showed that CFI-400945 associated with alisertib significantly decreased the concentration of both inhibitors needed to affect proliferation and viability in all cell lines tested. While alisertib alone required 200-500nM and CFI-400945 alone required 3.000–6.000nM to inhibit 50% proliferation and viability (IC50), combination of the two drugs required only 10-40nM of alisertib (13–20 times less) and 5-10nM of CFI-400945 (over 500 times less) to produce the same effect (p-value<0.001 in at least two cell lines for each assay). CONCLUSIONS The PLK4i acts synergistically with alisertib to target RT cells. This association can represent a novel, less toxic strategy to treat AT/RT. SUPPORT The Musella Foundation for Cancer Research.

SUBMITTER: Bailey A

PROVIDER: S-EPMC6011979 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Project description:Abstract Brain tumor diagnostics is achieved by combining morphology assessment and biomarker identification. However, the inter-observer variability of the histopathological diagnosis and lack of distinctive biomarkers makes these diagnoses particularly challenging. Recently, the potential for methylation-based characterization has been developed for brain tumors. To provide accurate and efficient brain tumor diagnostics, The Jackson Laboratory developed a DNA methylation array (Illumina Infinium HD Methylation EPIC), combining the “Classifier” established by the German Cancer Research Center (DKFZ), which can identify 82 distinct central nervous system tumors. Here we present a pediatric patient referred to us for medulloblastoma subtype classification by the methylation profile. Surprisingly, the array classified the tumor type as atypical teratoid/rhabdoid tumor (ATRT), subclass SHH. Also, the CNV profile indicated the SMARCB1/INI1 heterozygous deletion as part of the chromosome 22q deletion typically seen in ATRT, and absent was the isochromosome 17q commonly associated with medulloblastoma. Immunohistochemistry confirmed the loss of SMARCB1/INI1 expression leading to ATRT. Additionally, our NGS panel found a novel SMARCB1/INI1 frameshift variant c.1150delG (p.Ala384fs) in the last exon (exon 9). Although this variant is not expected to induce nonsense-mediated mRNA decay, it is located in the ATP-dependent nucleosome-remodeling complex domain Sfh1/SNF5 (IPR017393), which is associated with cell proliferation and differentiation. In addition, ClinVar reported several pathogenic/likely pathogenic variants in this domain, further supporting SMARCB1/INI1 c.1150delG which, together with the SMARCB1/INI1 deletion, may contribute to the loss of SMARCB1/INI1 expression, resulting in ATRT. We have identified the ATRT misclassification by the methylation profile and characterized a novel SMARCB1/INI1 variant c.1150delG most likely contributing to ATRT. We further propose that the DNA methylation profile will significantly improve the brain tumor diagnostics for cases with ambiguous, or contradictory histology and molecular profiles.

Project description:Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

Dataset Information

ATRT-02. THE AURORA KINASE A (AURKA) INHIBITOR ALISERTIB ACTS SYNERGISTICALLY WITH A POLO-LIKE KINASE 4 (PLK4) INHIBITOR TO TARGET ATYPICAL TERATOID / RHABDOID TUMOR (AT/RT) CELLS

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