75. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie

Prof. Dr.

Vorsitz

Prof. Dr. med.

Combinatorial drug screening identifies carfilzomib and enzalutamide for the treatment of aggressive meningiomas

Tumor

Medikamenten-Kombinationsscreening identifiziert Carfilzomib und Enzalutemid für die Behandlung von aggressiven Meningeomen.

The goal of combinatorial therapy is to improve the effectiveness of treatment by targeting multiple aspects of cancer cells or overcoming resistance to single drugs. In search of effective synergistic drug combinations for the treatment of meningiomas, we performed an automated combinatorial drug screening in meningioma cell lines and patient-derived tumor organoids.Three grade 3 meningioma cell lines (NCH93, IOMM-Lee, and KT21-MG1) were stably transduced with blue, green, and red fluorescence proteins. The cell lines were multiplexed into 384-well plates and treated in 5x5 dose-response (0-1000 nmol/l) matrices for 48 h by the automated liquid handler Hamilton MicroLAB STAR®. The drug library consisted of 166 FDA-approved anticancer drugs. To demultiplex cell viability from a single well, the fluorescence signal was used as a surrogate marker for viability. Patient-derived tumor organoids (TOs) were established from single cell suspensions of freshly resected meningioma tissue (total n=20; grade 2 n=1; n=3 recurrent tumors). The cell viability was measured by CellTiterGlo3D. Drug synergism was calculated by the ZIP synergy finder model.This drug screening effort generated 13,695 unique drug-drug combinations per cell line. Most synergistic combinations were observed in IOMM-Lee (n=157, 1.14%), followed by KT21-MG1 (n=122, 0.88%), and NCH93 (n=75, 0.54%). Next, we validated the 110 most effective drug combinations in wild-type meningioma cells. 75 drug combinations demonstrated a positive most synergistic area (MSA) score, indicating synergistic effects. Next, we selected the 16 most promising combinations based on synergy scores and literature evidence for screening in TOs. The drug combination of proteasome inhibitor carfilzomib and the androgen receptor inhibitor enzalutamide exhibited the highest MSA scores in TOs. In 40% (n=8/20) of the cases, the combination showed strong synergism (MSA>10) resulting in an overall average MSA of 7.36. This was followed by carfilzomib and neratinib, and romidepsin and gemcitabine with average MSAs of 5.49, and 4.32, respectively. Furthermore, carfilzomib and enzalutamide induced apoptosis in TOs assessed by Caspase-3/7 (p<0.01).This comprehensive combinatorial drug screening identified the synergistic combination of the proteasome inhibitor carfilzomib and androgen receptor inhibitor enzalutamide that can be an effective treatment option for selected meningioma patients.

Abstractvortrag | Abstract talk

Professor

Molecular characterization and genomic divergence in sporadic multiple meningiomas

Molekulare Muster und genomische Divergenz bei sporadischen multiplen Meningeomen

Multiple meningiomas are rare and pose distinct management challenges. While the mutational landscape of single meningiomas has been extensively explored, the molecular pathogenesis of sporadic multiple meningiomas is not fully understood. The objective of this study is to elucidate the genetic characteristics of sporadic multiple meningiomas.In our retrospective cohort from 2002 onwards, we identified 24 patients who underwent surgery for at least two sporadic separated meningiomas, totaling 57 meningiomas. Neurofibromatosis type 2 was excluded in all cases. We examined the genetic alterations in these tumors using a next generation sequencing (NGS), targeting a comprehensive set of genes frequently mutated in meningiomas, including AKT1, ATRX, CDKN2A, KLF4, NF1, NF2, PIK3CA, PIK3R1, POLR2A, PTEN, SMARCB1, SMO, STAG2, SUFU, TP53, TRAF7, and the TERT promotor. A radiological evaluation of MRI scans took place, applying a software with an automatic algorithm for segmentation (Brainlab AG, Munich, Germany).The average age at initial diagnosis was 57 years (ranging from 34 to 82 years). The majority of these multiple meningiomas (94.7%) were classified as WHO grade 1. Within individual patients, no shared driver mutations were observed between separate tumors. Nearly all cases exhibited distinct hot spot mutations in well-known meningioma-driver genes, including TRAF7 (n=14), NF2 (n=9), KLF4 (n=5), PIK3CA (n=4), AKT1 (n=4), NF1 (n=1), SMO (n=2), SMARCB1 (n=1), POLR2A (n=1), PTEN (n=2), and the TERT promoter (n=1). Furthermore, meningiomas from the same patient frequently presented as different histopathological subtypes. Consistent with previous studies, separate tumors from the same patient displayed different driver mutations, suggesting independent origins and distinct genomic drivers. The review of an average of 2.6 MRI scans conducted prior to surgery revealed a median preoperative tumor size of 12.14 cm³ (ranging from 0.33 to 122 cm³). The smallest meningioma were those, which harbored a TRAF7 mutation (range from 0.33 to 36 cm³, average volume 5.7 cm³), while the largest meningiomas exhibited a NF2 mutation (range from 0.72 to 122 cm³, average volume 59.6 cm³).Overall, our molecular analysis supports the notion of genomic divergence and the presumed independent origin of sporadic multiple meningiomas. This condition seems to exhibit both inter- and intra-personal heterogeneity.

Prof.

Genetic characterization and clinical features of olfactory groove meningiomas: A multi-institutional study

Genetische Charakterisierung und klinische Merkmale von Olfaktoriusrinnenmeningeomen: eine multizentrische Studie

This study aims to explore the link between the clinical and radiological characteristics of olfactory groove meningiomas (OGM) and their molecular profiles, with a focus on identifying oncogenic mutations through genomic studies.We conducted targeted next-generation sequencing on 119 OGM samples from three international institutions, covering key meningioma genes. We then compared the molecular findings with clinical and radiographic features of the tumors. Additionally, we retrospectively collected and analyzed patient and tumor data, including age, sex, radiological features, and tumor location.Our cohort included 76 females and 33 males. Most tumors (106 out of 119, 89%) were classified as WHO grade 1 meningioma, with the rest being WHO grade 2 and 3. Notably, 87.5% of patients (104 out of 119) had significant driver mutations. The most frequent mutations were SMO/SUFU (35 cases, 29.4%) und AKT1 (34 cases, 28.5%), followed by PIK3CA/PIK3R1 (16 cases, 13.4%), TRAF7 alone (7 cases, 5.9%), POLR2A (4 cases, 3.4%), and TRAF7/KLF4 (3 cases, 2.5%). The median age at diagnosis was 62 years (range 25-87 years), with PIK3CA-mutant patients being the youngest group (median age 52, range 29-78 years). The sex distribution across all molecular groups was similar (female to male ratio of 2.1:1). The average overall survival was 154.9 months (95% confidence interval [CI]: 123.7 – 165 months). Patients with SMO mutations had significantly lower survival (average 92.6 months, 95% CI: 72.5 – 112.7 months) compared to those with AKT1 mutations (average 150 months, 95% CI: 150.1 – 136.9 months, p= 0.008). The median tumor volume at initial diagnosis was 16,500 mm3. SMO-mutant OGMs had the largest median tumor volume (19,102 mm3), followed by PI3K-mutant OGMs (13,500 mm3). AKT1-mutant and TRAF7/KLF4-mutant OGMs had the smallest volumes (7,587 mm3 and 3,300 mm3, respectively).Our findings confirm the presence of significant actionable mutations in most OGM cases. The association of specific genetic alterations with tumor characteristics could have important implications for developing personalized treatment strategies in the future.

The pharmacological atlas of meningiomas

Erstellung eines pharmakologischen Atlas von Meningeomen

There are no systemic treatment options for patients with recurrent or refractory meningioma. The objective is to create a pharmacological atlas of all FDA-approved oncology drugs in a large cohort of patient-derived meningioma organoids.Patient-derived meningioma organoids (TOs) were generated from single cell suspensions from freshly resected meningiomas. TOs were treated with semi-logarithmic concentrations spanning from 10 nmol/l to 30 µmol/l by the automated liquid handler Hamilton MicroLAB STAR®. The drug library AODX from the National Cancer Institute consisted of 179 FDA-approved anticancer drugs. The viability was measured with the RealTimeGlo (Promega). Half-maximal inhibitory concentrations (IC50) were calculated by GraphPad Prism software. Categorization into sensitive and resistant drug–response groups was based on the IC50 values and each drug"s peak serum concentration (Cmax).We created a pharmacological atlas of meningiomas by generating dose-response curves of all 179 current FDA-approved oncology drugs in patient-derived tumor organoids from 32 meningioma patients. The cohort consisted of 28 WHO grade 1, and 4 grade 2 meningiomas, including 4 recurrent tumors. In total, 27% (n=50/179) of the drugs demonstrated a median IC50 value below 30 µmol/l, with specific and significant enrichment for topoisomerase, RNA/protein synthesis, proteasome, mTOR, and HDAC inhibitors. The top five drugs with the lowest IC50 values were romidepsin, dactinomycin, carfilzomib, plicamycin, and omacetaxine with median values of 10, 27, 170, 326, and 330 nmol/l. Dimension reduction methods of IC50 data revealed somehow linear changes in drug sensitivities between meningiomas rather than drug sensitivity clusters. When considering the Cmax/IC50 ratio as a potential predictive marker of treatment response (>1), the HDAC inhibitors belinostat (74.5), romidepsin (69.7), the proteasome inhibitor carfilzomib (34.6), and the anthracycline epirubicin (2.6), and doxorubicin (1.8), and the PI3K inhibitor idelalisib (1.6) are the most promising drug candidates for further in/ex vivo evaluation.We provide the first comprehensive insight into the pharmacological landscape of meningiomas. This data might serve as the foundation for future clinical studies on the systemic treatment of aggressive meningiomas.

Trends for survival and functional recovery in radiation-induced meningiomas

Trends für Überleben und funktionelle Erholung bei strahleninduzierten Meningeomen

Meningiomas are the most common intracranial neoplasms, accounting for 37.6% of intracranial malignancies. Rarely, tumorigenesis might be induced by radiotherapy, which is often used in the setting of pediatric central nervous system (CNS) malignancies. Although radiation-induced meningiomas are a known complication of CNS radiotherapy, there is a paucity of information to guide treatment decisions. This study aimed to determine the clinical characteristics of radiation-induced meningiomas, recurrence and postoperative functional status.A single-center retrospective study including patients undergoing resection of intracranial meningiomas between 2007 and 2018 was performed. Patients with intracranial radiation exposure were identified using hospital records and compared with non-radiation induced cases. We performed 1:3 propensity score matching between patients being exposed to radiotherapy and non-exposed patients using WHO grade, Simpson class and age. Comparison between the groups was performed using Mann-Whitney, Chi-Squared test and Cox regression analysis.During this period 841 meningioma patients with sufficient medical records were identified. Radiation-induced meningiomas were present in 33 cases. Propensity score matching with 99 unexposed cases resulted in homogeneous, comparable groups with respect to the variables used. Mean age at diagnosis was 25.8±12.6 years, mean CCI was 1.4±1.5. WHO grade 1 tumors were present in 63.63%, grade 2 in 33.3% and grade 3 in 3.03% of cases. Simpson class 1 resection was achieved in 42.42%, 2 in 18.93%, 3 in 17.42% and 4 in 21.21%. There was better recovery of functional status at 6 months and at last follow-up (mean KPS -1.59 vs -2.24 p<0.001; 2.98 vs -2.58 p<0.001) but the clinical relevance is questionable. Median 5-year progression free survival was significantly lower in radiation exposed cases (43.5 vs 62.1% p=0.035). In multivariate Cox regression analysis, radiation exposure (HR 2.58 95%CI 1.29-5 p=0.008) and WHO grade (2.04 95%CI 1.09-3.8 p=0.025) were the only significant risk factors for recurrence.In our age, Simpson- and CNS WHO-grade matched cohort, radiation-induced meningiomas exhibited a shorter progression-free survival compared to naïve tumors, independent of known predictors. This suggests unknown differences in pathogenesis requiring further scrutiny.

Targeting tumor-associated macrophages in the immune-microenvironment of meningiomas

Zielgerichtete Therapie gegen Tumor-assoziierte Makrophagen im Immun-Microenvironment von Meningeomen

Meningioma represents the most common primary brain malignancy in adults with a subset of tumors exhibiting aggressive clinical behavior. Immunotherapy might present a new treatment strategy but is highly dependent on the immunological composition of the tumor microenvironment. Our previous data have shown that tumor-associated macrophages (TAMs) make up the main immune cell population in meningiomas with a negative impact on patient outcome. In this study, we investigated whether TAMs from meningioma tissue can be reprogrammed to an immunologically active and tumoricidal phenotype.CD11b+ sorted macrophages derived from tumor samples from > 40 patients including clinically aggressive meningiomas were treated with small molecule inhibitors targeting the colony-stimulating factor-1 receptor (CSF-1R). In a first analysis, the direct treatment response of patient-derived macrophages has been investigated by various techniques including flow cytometry and bulk RNA-sequencing of treated TAMs and further analysis of the macrophage-conditioned media after treatment. In addition, we studied the influence of CSF-1R-targeted macrophage treatment on the phenotype and functional activity of T cells to assess a potential indirect treatment response in the tumor microenvironment.Our data revealed that CSF-1R-targeted treatment of CD11b+ TAMs induced significant changes in the protein and gene expression of macrophage polarization markers towards a more immunologically active state and a significantly higher metabolic nitric oxide production as another sign of immunological activation. Subsequent analysis of indirect effects on T cells showed not only a significantly increased expression of the T cell activation marker CD69+, but also a significantly increased tumor cell killing by autologous T cells after macrophage-targeted treatment.Together these data suggest both a direct and indirect CSF-1R-targeted macrophage treatment response in the local tumor microenvironment and give first promising results on the efficacy of macrophage-targeted immunotherapy in human meningiomas.

Session 12
Tumor – Meningiome

Appointment

Vorsitz

Topic

Programme