High-Throughput Drug Screening Identifies Pazopanib and Clofilium Tosylate as Promising Treatments for Malignant Rhabdoid Tumors

Summary: Rhabdoid tumors (RTs) are aggressive tumors of early childhood characterized by SMARCB1 inactivation. Their poor prognosis highlights an urgent need to develop new therapies. Here, we performed a high-throughput screening of approved drugs and identified broad inhibitors of tyrosine kinase receptors (RTKs), including pazopanib, and the potassium channel inhibitor clofilium tosylate (CfT), as SMARCB1-dependent candidates. Pazopanib targets were identified as PDGFRα/β and FGFR2, which were the most highly expressed RTKs in a set of primary tumors. Combined genetic inhibition of both these RTKs only partially recapitulated the effect of pazopanib, emphasizing the requirement for broad inhibition. CfT perturbed protein metabolism and endoplasmic reticulum stress and, in combination with pazopanib, induced apoptosis of RT cells in vitro. In vivo, reduction of tumor growth by pazopanib was enhanced in combination with CfT, matching the efficiency of conventional chemotherapy. These results strongly support testing pazopanib/CfT combination therapy in future clinical trials for RTs. : Rhabdoid tumors (RTs) are aggressive pediatric tumors characterized by SMARCB1 inactivation. Chauvin et al. identify two SMARCB1-dependent targeted therapies for RT: pazopanib, which inhibits PDGFR and FGFR2, and the potassium channel inhibitor clofilium tosylate, which induces endoplasmic reticulum stress. Combining both drugs induces cell apoptosis and reduces PDX tumor growth. Keywords: rhabdoid tumors, SMARCB1, pazopanib, clofilium tosylate, high-throughput drug screening, tyrosine kinase inhibitor

Optimising biomarkers for accurate ependymoma diagnosis, prognostication and stratification within International Clinical Trials: A BIOMECA study

BACKGROUND: Accurate identification of brain tumour molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study. METHODS: Across six European BIOMECA laboratories we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via FISH and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH. RESULTS: DNA Methylation profiling classified 65.3% (n=96/147) of cases as EPN-PFA and 15% (n=22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99-100% across three centres). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP1- fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-centre concordance and low sensitivity and specificity whilst MIP, MLPA and DNA methylation-based approaches demonstrated greater accuracy. CONCLUSIONS: We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q and CDKN2A loss whilst FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches

MBCL-43 pronostic factors for overall survival after recurrence in childhood medulloblastoma

info:eu-repo/semantics/publishe

Predictors of early postoperative epileptic seizures after awake surgery in supratentorial diffuse gliomas

International audienceObjective: Functional-based resection under awake conditions had been associated with a nonnegligible rate of intraoperative and postoperative epileptic seizures. The authors assessed the incidence of intraoperative and early postoperative epileptic seizures after functional-based resection under awake conditions.Methods: The authors prospectively assessed intraoperative and postoperative seizures (within 1 month) together with clinical, imaging, surgical, histopathological, and follow-up data for 202 consecutive diffuse glioma adult patients who underwent a functional-based resection under awake conditions.Results: Intraoperative seizures occurred in 3.5% of patients during cortical stimulation; all resolved without any procedure being discontinued. No predictor of intraoperative seizures was identified. Early postoperative seizures occurred in 7.9% of patients at a mean of 5.1 ± 2.9 days. They increased the duration of hospital stay (p = 0.018), did not impact the 6-month (median 95 vs 100, p = 0.740) or the 2-year (median 100 vs 100, p = 0.243) postoperative Karnofsky Performance Status score and did not impact the 6-month (100% vs 91.4%, p = 0.252) or the 2-year (91.7 vs 89.4%, p = 0.857) postoperative seizure control. The time to treatment of at least 3 months (adjusted OR [aOR] 4.76 [95% CI 1.38-16.36], p = 0.013), frontal lobe involvement (aOR 4.88 [95% CI 1.25-19.03], p = 0.023), current intensity for intraoperative mapping of at least 3 mA (aOR 4.11 [95% CI 1.17-14.49], p = 0.028), and supratotal resection (aOR 6.24 [95% CI 1.43-27.29], p = 0.015) were independently associated with early postoperative seizures.Conclusions: Functional-based resection under awake conditions can be safely performed with a very low rate of intraoperative and early postoperative seizures and good 6-month and 2-year postoperative seizure outcomes. Intraoperatively, the use of the lowest current threshold producing reproducible responses is mandatory to reduce seizure occurrence intraoperatively and in the early postoperative period

Prognostic relevance of adding MRI data to WHO 2016 and cIMPACT‐NOW updates for diffuse astrocytic tumors in adults. Working toward the extended use of MRI data in integrated glioma diagnosis

International audienceAssess the contribution of preoperative MRI data in improving grading of adult astrocytomas reclassified according to the WHO 2016 and cIMPACT-NOW update 3. Retrospective unicentric cohort study of 679 adult patients treated for newly diagnosed diffuse astrocytic and oligodendroglial tumors (January 2006-December 2016). We first systematically compared radiological (contrast enhancement present [CE+] vs. absent [CE-]) and histopathological findings (microvascular proliferation present [MPV+] vs. absent [MPV-]) to validate whether this comparing step of neoangiogenesis represents an efficient method to appreciate the representativity of the tumoral sampling. We focused on 629 cases of astrocytomas for radio-histological integrated analyses. In 598 cases (95.1%), neoangiogenesis evaluated by MRI or histology (CE+/MPV+ or CE-/MPV-) was identical. For the CE+/MPV- and CE-/MPV+ groups (23 cases), the radio-histological face-to-face evaluation allowed us to assess that for 13 cases (56.5%) the reason for this discrepancy was an undersampled tumor. We analyzed the group of CE+/MPV- (n = 8) and CE-/MPV+ (n = 2) in verified image-guided tumoral samples. Finally, we identified three new prognostic subgroups for molecular glioblastomas: (1) "non-representative sampling" (n = 9), (2) "Non neoangiogenic glioblastoma at the time of diagnosis, without contrast enhancement and microvascular proliferation" (n = 8), and (3) "contrast enhancing glioblastoma but without microvascular proliferation in a representative sample" (n = 4). Neoangiogenesis processes should be assessed to improve the prognosis accuracy of the current integrated diagnosis. We suggest adding imaging analyses during the neuropathological analysis of astrocytomas in adults

Imaging growth as a predictor of grade of malignancy and aggressiveness of IDH-mutant and 1p/19q-codeleted oligodendrogliomas in adults

International audienceWe quantified the spontaneous imaging growth rate of oligodendrogliomas. We assessed whether (i) it discriminates between World Health Organization (WHO) grade II and grade III oligodendrogliomas, and (ii) grade III oligodendrogliomas with neo-angiogenesis are associated with more fast growth rates (≥8 mm/y)

Papillary glioneuronal tumors: histological and molecular characteristics and diagnostic value of SLC44A1-PRKCA fusion.

CERVOXY COLLInternational audienc

Diffuse midline glioma invasion and metastasis rely on cell-autonomous signaling

International audienceAbstract Background Diffuse midline gliomas (DMG) are pediatric tumors with negligible 2-year survival after diagnosis characterized by their ability to infiltrate the central nervous system. In the hope of controlling the local growth and slowing the disease, all patients receive radiotherapy. However, distant progression occurs frequently in DMG patients. Current clues as to what causes tumor infiltration circle mainly around the tumor microenvironment, but there are currently no known determinants to predict the degree of invasiveness. Methods In this study, we use patient-derived glioma stem cells (GSCs) to create patient-specific 3D avatars to model interindividual invasion and elucidate the cellular supporting mechanisms. Results We show that GSC models in 3D mirror the invasive behavior of the parental tumors, thus proving the ability of DMG to infiltrate as an autonomous characteristic of tumor cells. Furthermore, we distinguished 2 modes of migration, mesenchymal and ameboid-like, and associated the ameboid-like modality with GSCs derived from the most invasive tumors. Using transcriptomics of both organoids and primary tumors, we further characterized the invasive ameboid-like tumors as oligodendrocyte progenitor-like, with highly contractile cytoskeleton and reduced adhesion ability driven by crucial over-expression of bone morphogenetic pathway 7 (BMP7). Finally, we deciphered MEK, ERK, and Rho/ROCK kinases activated downstream of the BMP7 stimulation as actionable targets controlling tumor cell motility. Conclusions Our findings identify 2 new therapeutic avenues. First, patient-derived GSCs represent a predictive tool for patient stratification in order to adapt irradiation strategies. Second, autocrine and short-range BMP7-related signaling becomes a druggable target to prevent DMG spread and metastasis