TY  - JOUR
AB  - BACKGROUND: The diffuse growth pattern of glioblastoma is one of the main challenges for accurate treatment. Computational tumor growth modeling has emerged as a promising tool to guide personalized therapy. Here, we performed clinical and biological validation of a novel growth model, aiming to close the gap between the experimental state and clinical implementation. METHODS: One hundred and twenty-four patients from The Cancer Genome Archive (TCGA) and 397 patients from the UCSF Glioma Dataset were assessed for significant correlations between clinical data, genetic pathway activation maps (generated with PARADIGM; TCGA only), and infiltration (Dw) as well as proliferation (ρ) parameters stemming from a Fisher-Kolmogorov growth model. To further evaluate clinical potential, we performed the same growth modeling on preoperative magnetic resonance imaging data from 30 patients of our institution and compared model-derived tumor volume and recurrence coverage with standard radiotherapy plans. RESULTS: The parameter ratio Dw/ρ (P < .05 in TCGA) as well as the simulated tumor volume (P < .05 in TCGA/UCSF) were significantly inversely correlated with overall survival. Interestingly, we found a significant correlation between 11 proliferation pathways and the estimated proliferation parameter. Depending on the cutoff value for tumor cell density, we observed a significant improvement in recurrence coverage without significantly increased radiation volume utilizing model-derived target volumes instead of standard radiation plans. CONCLUSIONS: Identifying a significant correlation between computed growth parameters and clinical and biological data, we highlight the potential of tumor growth modeling for individualized therapy of glioblastoma. This might improve the accuracy of radiation planning in the near future.
AU  - Metz, M.C.*
AU  - Ezhov, I.*
AU  - Peeken, J.C.
AU  - Buchner, J.A.*
AU  - Lipkova, J.*
AU  - Kofler, F.
AU  - Waldmannstetter, D.*
AU  - Delbridge, C.*
AU  - Diehl, C.*
AU  - Bernhardt, D.
AU  - Schmidt-Graf, F.*
AU  - Gempt, J.*
AU  - Combs, S.E.
AU  - Zimmer, C.*
AU  - Menze, B.*
AU  - Wiestler, B.*
C1  - 70086
C2  - 55016
CY  - Great Clarendon St, Oxford Ox2 6dp, England
TI  - Toward image-based personalization of glioblastoma therapy: A clinical and biological validation study of a novel, deep learning-driven tumor growth model.
JO  - Neurooncol. Adv.
VL  - 6
IS  - 1
PB  - Oxford Univ Press
PY  - 2024
SN  - 2632-2498
ER  - 

TY  - JOUR
AB  - Background: The oncogene epidermal growth factor receptor variant III (EGFRvIII) is expressed in approximately one-third of all glioblastomas (GBMs). So far it is not clear if EGFRvIII expression induces replication stress in GBM cells, which might serve as a therapeutical target. Methods: Isogenetic EGFRvIII- and EGFRvIII+ cell lines with endogenous EGFRvIII expression were used. Markers of oncogenic and replication stress such as γH2AX, RPA, 53BP1, ATR, and CHK1 were analyzed using western blot, immunofluorescence, and flow cytometry. The DNA fiber assay was performed to analyze replication, transcription was measured by incorporation of EU, and genomic instability was investigated by micronuclei and CGH-Array analysis. Immunohistochemistry staining was used to detect replication stress markers and R-loops in human GBM samples. Results: EGFRvIII+ cells exhibit an activated replication stress response, increased spontaneous DNA damage, elevated levels of single-stranded DNA, and reduced DNA replication velocity, which are all indicative characteristics of replication stress. Furthermore, we show here that EGFRvIII expression is linked to increased genomic instability. EGFRvIII-expressing cells display elevated RNA synthesis and R-loop formation, which could also be confirmed in EGFRvIII-positive GBM patient samples. Targeting replication stress by irinotecan resulted in increased sensitivity of EGFRvIII+ cells. Conclusion: This study demonstrates that EGFRvIII expression is associated with increased replication stress, R-loop accumulation, and genomic instability. This might contribute to intratumoral heterogeneity but may also be exploited for individualized therapy approaches.
AU  - Struve, N.*
AU  - Hoffer, K.*
AU  - Weik, A.S.*
AU  - Riepen, B.*
AU  - Krug, L.*
AU  - Cetin, M.H.*
AU  - Burmester, J.*
AU  - Ott, L.*
AU  - Liebing, J.*
AU  - Gatzemeier, F.*
AU  - Müller-Goebel, J.*
AU  - Gerbach, M.*
AU  - Bußmann, L.*
AU  - Parplys, A.C.*
AU  - Unger, K.
AU  - Mansour, W.Y.*
AU  - Schüller, U.*
AU  - Rieckmann, T.*
AU  - Petersen, C.*
AU  - Rothkamm, K.*
AU  - Short, S.C.*
AU  - Kriegs, M.*
C1  - 64649
C2  - 51891
TI  - Increased replication stress and R-loop accumulation in EGFRvIII-expressing glioblastoma present new therapeutic opportunities.
JO  - Neurooncol. Adv.
VL  - 4
IS  - 1
PY  - 2022
SN  - 2632-2498
ER  - 

TY  - JOUR
AB  - Background: The potential benefit of risk stratification using a 4-miRNA signature in combination with MGMT promoter methylation in IDH1/2 wild-type glioblastoma patients was assessed. Methods: Primary tumors from 102 patients with comparable treatment from the LMU Munich (n = 37), the University Hospital Düsseldorf (n = 33), and The Cancer Genome Atlas (n = 32) were included. Risk groups were built using expressions of hsa-let-7a-5p, hsa-let-7b-5p, hsa-miR-615-5p, and hsa-miR-125a-5p to assess prognostic performance in overall survival (OS). MGMT promoter methylation and age were considered as cofactors. Integrated miRNA, DNA methylome, and transcriptome analysis were used to explore the functional impact of signature miRNAs. Results: The 4-miRNA signature defined high-risk (n = 46, median OS: 15.8 months) and low-risk patients (n = 56, median OS: 20.7 months; univariable Cox proportional hazard analysis: hazard ratio [HR]: 1.8, 95% confidence interval [CI]: 1.14-2.83, P = .01). The multivariable Cox proportional hazard model including the 4-miRNA signature (P = .161), MGMT promoter methylation (P < .001), and age (P = .034) significantly predicted OS (Log-rank P < .0001). Likewise to clinical routine, analysis was performed for younger (≤60 years, n = 50, median OS: 20.2 months) and older patients (>60 years, n = 52, median OS: 15.8) separately. In younger patients, the 4-miRNA signature had prognostic value (HR: 1.92, 95% CI: 0.93-3.93, P = .076). Particularly, younger, MGMT methylated, 4-miRNA signature low-risk patients (n = 18, median OS: 37.4 months) showed significantly improved survival, compared to other younger patients (n = 32, OS 18.5 months; HR: 0.33, 95% CI: 0.15-0.71, P = .003). Integrated data analysis revealed 4-miRNA signature-associated genes and pathways. Conclusion: The prognostic 4-miRNA signature in combination with MGMT promoter methylation improved risk stratification with the potential for therapeutic substratification, especially of younger patients.
AU  - Unger, K.
AU  - Fleischmann, D.F.*
AU  - Ruf, V.*
AU  - Felsberg, J.*
AU  - Piehlmaier, D.
AU  - Samaga, D.
AU  - Hess J.
AU  - Suresh, M.P.*
AU  - Mittelbronn, M.*
AU  - Lauber, K.
AU  - Budach, W.*
AU  - Säbel, M.*
AU  - Rödel, C.*
AU  - Reifenberger, G.*
AU  - Herms, J.*
AU  - Tonn, J.C.*
AU  - Zitzelsberger, H.
AU  - Belka, C.
AU  - Niyazi, M.*
C1  - 60760
C2  - 49538
TI  - Improved risk stratification in younger IDH wild-type glioblastoma patients by combining a 4-miRNA signature with MGMT promoter methylation status.
JO  - Neurooncol. Adv.
VL  - 2
IS  - 1
PY  - 2020
SN  - 2632-2498
ER  -