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A series of chiral sulfonamides containing the 2-azabicycloalkane scaffold were prepared from aza-Diels–Alder cycloadducts through their conversion to amines based on 2-azanorbornane or the bridged azepane skeleton, followed by the reaction with sulfonyl chlorides. The cytotoxic activity of the obtained bicyclic derivatives was evaluated using human hepatocellular carcinoma (HCC), medulloblastoma (MB), and glioblastoma (GBM) cell lines. Chosen compounds were shown to notably reduce cell viability as compared to nonmalignant cells.

High-grade gliomas (HGGs) are the most aggressive adult brain tumors, with a dismal median survival of approximately 15 months, highlighting the need for novel therapeutic strategies. In a prior immunotherapy trial using dendritic cells against glioblastoma, miR-216b emerged as a potential predictive biomarker. Thus, we hypothesize that miR-216b impacts glioma aggressiveness and thereby therapeutic success. Here, we demonstrate that miR-216b is significantly downregulated in the majority of Isocitrate dehydrogenase 1/2 (IDH) wild-type HGG tissue samples (n = 42) and cell models (n = 18). Functional assays revealed that miR-216b overexpression impairs glioma cell proliferation, migration, and stemness characteristics. Transcriptomic and target prediction analyses identified CDK4 , a key cell cycle regulator, as a direct target of miR-216b, confirmed via luciferase reporter assays. Correspondingly, upregulating miR-216b (mimic) via transfection decreased CDK4 mRNA and protein levels accompanied by a p21-dependent increase of cells in G0/G1 phase. In addition, miR-216b expression correlated with increased sensitivity to the CDK4/6 inhibitor Abemaciclib. Notably, miR-216b levels were significantly higher in less aggressive IDH-mutant gliomas (n = 21), linking its downregulation to malignancy grade. Collectively, our findings discovered miR-216b as a tumor suppressor in HGGs, modulating CDK4 expression and affecting the responsiveness to CDK4/6 inhibitors. The observed results support the potential of miR-216b as both a prognostic and predictive indicator in HGGs.

Since cancer cells, when grown as spheroids, display drug sensitivity and radiation resistance patterns such as seen in vivo we recently established a three-dimensional (3D) in vitro model recapitulating colorectal cancer (CRC)-triggered lymphatic endothelial cell (LEC)-barrier breaching to study mechanisms of intra-/extravasation. CRC metastasizes not only through lymphatics but also through blood vessels and here we extend the 3D model to the interaction of blood endothelial cells (BECs) with naïve and 5-fluorouracil (5-FU)-resistant CRC CCL227 cells. The 3D model enabled quantifying effects of tumour-derived microRNA200 (miR200) miR200a, miR200b, miR200c, miR141 and miR429 regarding the induction of so-called 'circular chemorepellent-induced defects' (CCIDs) within the BEC-barrier, which resemble gates for tumour transmigration. For this, miR200 precursors were individually transfected and furthermore, the modulation of ZEB family expression was analysed by western blotting. miR200c, miR141 and miR429, which are contained in exosomes from naïve CCL227 cells, downregulated the expression of ZEB2, SNAI and TWIST in BECs. The exosomes of 5-FU-resistant CCL227-RH cells, which are devoid of miR200, accelerated CCID formation in BEC monolayers as compared to exosomes from naïve CCL227 cells. This confirmed the reported role of ZEB2 and SNAI in CRC metastasis and highlighted the active contribution of the stroma in the metastatic process. CCL227 spheroids affected the integrity of BEC and LEC barriers alike, which was in agreement with the observation that CRC metastasizes via blood stream (into the liver) as well as via lymphatics (into lymph nodes and lungs). This further validated the CRC/LEC and CRC/BEC in vitro model to study mechanisms of CRC spreading through vascular systems. Treatment of CCL227-RH cells with the HDAC inhibitors mocetinostat and sulforaphane reduced CCID formation to the level triggered by naïve CCL227 spheroids, however, without significantly influencing miR200 expression in CCL227-RH cells.

Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management. However, the optimal strategy for monitoring gliomas by LB remains to be determined. In this study, we analyzed circulating tumor DNA (ctDNA) from 78 liquid biopsies (plasma n  = 44, cerebrospinal fluid n  = 34 (CSF)) of 35 glioma patients, determining H3F3A K28M (K27M) and BRAF V600E mutation allele frequency using droplet digital PCR (ddPCR). All results were correlated to clinically relevant parameters including diagnostic imaging and CSF aspiration site (ventricular vs lumbar) with respect to tumor localization. Regarding diagnostic accuracy, the calculated sensitivity score in the H3F3A K27M cohort was 84.61% for CSF and 73.68% for plasma. In the BRAF V600E cohort, we determined a sensitivity of 83.3% in plasma and 80% in CSF. The overall specificity was 100%. With respect to the CSF aspiration, the intra-operatively obtained CSF demonstrated 100% detection rate, followed by ventricular CSF obtained via Ommaya Reservoir/shunt puncture (93%) and CSF obtained via lumbar puncture (66%). Notably, this further correlated with the proximity of the CSF site to tumor localization. Longitudinal CSF monitoring demonstrated a good correlation to clinical and radiological disease evolution. Importantly, we show for the first time that monitoring BRAF V600E by ddPCR could serve as treatment response assessment in gliomas. In summary, our observation may inform recommendations with regard to location of CSF aspiration when incorporating LB into future treatment protocols.

Background To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF). Objective This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors. Patients and Methods Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5–27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab. Results Apart from in serum (minimum concentration/maximum concentration [ C min / C max ] 77.0–305/267–612 mg/L, median 144/417 mg/L), bevacizumab could be quantified in the CSF (0.01–2.26 mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL). Conclusions This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors.

N-Heterocycles are considered as desirable scaffolds for the development of novel lead compounds for anticancer drug research. Among them, phosphorus-containing amino-derivatives play a crucial role. A series of imines and products of their further reactions with P-nucleophiles were obtained starting from vicinal bisamines. Reaction of ethylenediamine and α-carbonyl esters yielded in novel unexpected products, which structures were confirmed by crystallographic measurements. The cytotoxic activity evaluation was done on a variety of cell lines including HUH7, AKH12, DAOY, UW228-2, D283, D425, and U251. Human umbilical vein endothelial cells (HUVECs) were used as control. Two of the tested compounds, bearing TADDOL-derived, and trifluoromethyl substituents showed a significant effect on cell viability, though comparable to nonmalignant cells.

Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca 2+ levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca 2+ , Ca 2+ -calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca 2+ release. Thus, Ca 2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour–stroma interaction.

Medulloblastoma, an embryonal tumor of the cerebellum/fourth ventricle, is one of the most frequent malignant brain tumors in children. Although genetic variants are increasingly used in treatment stratification, survival of high-risk patients, characterized by leptomeningeal dissemination, TP53 mutation or MYC amplification, is still poor. FOXM1, a proliferation-specific oncogenic transcription factor, is deregulated in various solid tumors, including medulloblastoma, and triggers cellular proliferation, migration and genomic instability. In tissue samples obtained from medulloblastoma patients, the significant upregulation of FOXM1 was associated with a loss of its putative regulating microRNA, miR-4521. To understand the underlying mechanism, we investigated the effect of miR-4521 on the expression of the transcription factor FOXM1 in medulloblastoma cell lines. Transfection of this microRNA reduced proliferation and invasion of several medulloblastoma cell lines and induced programmed cell death through activation of caspase 3/7. Further, downstream targets of FOXM1 such as PLK1 and cyclin B1 were significantly reduced thus affecting the cell cycle progression in medulloblastoma cell lines. In conclusion, a restoration of miRNA-4521 may selectively suppress the pathophysiological effect of aberrant FOXM1 expression and serve as a targeted approach for medulloblastoma therapy.

Ependymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.