Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients

Zeiner, Pia S.; Kinzig, Martina; Divé, Iris; Maurer, Gabriele D.; Filipski, Katharina; Harter, Patrick N.; Senft, Christian; Bähr, Oliver; Hattingen, Elke; Steinbach, Joachim P.; Sörgel, Fritz; Voß, Martin; Steidl, Eike; Ronellenfitsch, Michael

doi:10.3390/jcm8122031

Cited by 28 publications

(34 citation statements)

References 40 publications

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“… 51 , 52 Of particular interest are the compounds teniposide, omacetaxine, and marizomib, which are reported to cross the BBB and may offer candidates for systemic delivery. 53–55 …”

Section: Discussionmentioning

confidence: 99%

Generation, characterization, and drug sensitivities of 12 patient-derived IDH1-mutant glioma cell cultures

Verheul

Ntafoulis

Kers

et al. 2021

Neuro-Oncology Advances

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Background Mutations of the isocitrate dehydrogenase (IDH) gene occur in over 80% of low-grade gliomas and secondary glioblastomas. Despite considerable efforts, endogenous in vitro IDH-mutated glioma models remain scarce. Availability of these models is key for the development of new therapeutic interventions. Methods Cell cultures were established from fresh tumor material and expanded in serum-free culture media. D-2-Hydroxyglutarate levels were determined by mass-spectrometry. Genomic and transcriptomic profiling were carried out on the Illumina Novaseq platform, methylation profiling was performed with the Infinium MethylationEpic BeadChip array. Mitochondrial respiration was measured with the Seahorse XF24 Analyzer. Drug screens were performed with an NIH FDA-approved anti-cancer drug set and two IDH-mutant specific inhibitors. Results A set of twelve patient-derived IDHmt cell cultures was established. We confirmed high concordance in driver mutations, copy number and methylation profiles between the tumors and derived cultures. Homozygous deletion of CDKN2A/B was observed in all cultures. IDH-mutant cultures had lower mitochondrial reserve capacity. IDH-mutant specific inhibitors did not affect cell viability or global gene expression. Screening of 107 FDA-approved anti-cancer drugs identified nine compounds with potent activity against IDHmt gliomas, including three compounds with favorable pharmacokinetic characteristics for CNS penetration: teniposide, omacetaxine mepesuccinate, and marizomib. Conclusions Our twelve IDH-mutant cell cultures show high similarity to the parental tissues and offer a unique tool to study the biology and drug sensitivities of high-grade IDHmt gliomas in vitro. Our drug screening studies reveal lack of sensitivity to IDHmt inhibitors, but sensitivity to a set of nine available anti-cancer agents.

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“… 51 , 52 Of particular interest are the compounds teniposide, omacetaxine, and marizomib, which are reported to cross the BBB and may offer candidates for systemic delivery. 53–55 …”

Section: Discussionmentioning

confidence: 99%

Generation, characterization, and drug sensitivities of 12 patient-derived IDH1-mutant glioma cell cultures

Verheul

Ntafoulis

Kers

et al. 2021

Neuro-Oncology Advances

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show abstract

“…However, the post-regorafenib variation in the mean ADC thus calculated did not signi cantly correlate with the corresponding change in FET-positive volume, nor with the RANO response categories. A possible explanation for this discrepancy may lie in the different methodological approaches used here and in the previously published studies [13,34,[43][44][45][35][36][37][38][39][40][41][42]. This highlights the importance of future efforts towards standardizing the analysis of ADC maps before considering the inclusion of this methodology in the response assessment criteria.…”

Section: Discussionmentioning

confidence: 83%

“…The predictive value of the low-ADC areas is con rmed by other published papers [36,37]. Zeiner et al [38] calculated the ADC-ratio by measuring the minimum ADC values in the tumor and normalizing them by the ADC values of the contralateral, normal appearing brain tissue. In our study, instead, a standard VOI contralateral to the lesion was used to determine the appropriate threshold for the selection of pathological ADC values.…”

Section: Discussionmentioning

confidence: 88%

Preliminary results using PET/MR in glioblastoma patients treated with regorafenib: an 18F-FET and DWI-ADC comparison

Spimpolo

Lombardi

Berti

et al. 2021

Preprint

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Introduction: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. DWI and 18F–FET PET are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in DWI/ADC- and 18F-FET PET-derived parameters in patients who underwent PET/MR at both baseline and soon after starting regorafenib. Method: We retrospectively selected 16 consecutive GBM patients who underwent 18F–FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze 4 SD patients who underwent a third PET/MR after another 4 cycles of regorafenib. 18F–FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and soon after treatment. A number of metrics were then derived and compared. Result: The average increases in FET and ADC pathological volumes were higher in PD than in SD patients, although in neither case did the difference reach significance. However, when the percentage difference in FET volumes was plotted against the corresponding percentage difference in ADC, a correlation was observed (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Conclusion: In recurrent glioblastoma patients treated with regorafenib, 18F-FET and ADC metrics, being obtained from completely different measures, could serve as semi-quantitative independent biomarkers of response to treatment. These promising parameters should be tested in a larger cohort of glioblastoma patients treated with regorafenib.

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“…The current developments in local or enhanced CNS delivery methods opens up new treatment possibilities for highly potent compounds that do not have favorable characteristics to pass the BBB, such as romidepsin and dactinomycin. 42,43 Of particular interest are the compounds teniposide, omacetaxine, and marizomib, which are reported to cross the BBB and may offer candidates for systemic delivery 44–46 .…”

Section: Discussionmentioning

confidence: 99%

Generation, characterization and drug sensitivities of twelve patient-derived IDH1 mutant glioma cell cultures

Verheul

Ntafoulis

Kers

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Mutations of the isocitrate dehydrogenase (IDH) gene occur in over 80% of low-grade gliomas and secondary glioblastomas. Despite considerable efforts, endogenous in vitro IDH-mutated glioma models remain scarce. Availability of these models is key for the development of new therapeutic interventions. Methods: Cell cultures were established from fresh tumor material and expanded in serum-free culture media. D-2-Hydroxyglutarate levels were determined by mass-spectrometry. Genomic and transcriptomic profiling were carried out on the Illumina Novaseq platform, methylation profiling was performed with the Infinium MethylationEpic BeadChip array. Mitochondrial respiration was measured with the Seahorse XF24 Analyzer. Drug screens were performed with an NIH FDA-approved anti-cancer drug set and two IDH-mutant specific inhibitors. Results: A set of twelve patient-derived IDHmt cell cultures were established. We confirmed high concordance in driver mutations, copy number and methylation profiles between the tumors and derived cultures. Homozygous deletion of CDKN2A/B was observed in all cultures. IDH-mutant cultures had lower mitochondrial reserve capacity. IDH-mutant specific inhibitors did not affect cell viability or global gene expression. Screening of 107 FDA-approved anti-cancer drugs identified nine compounds with potent activity against IDHmt gliomas, including three compounds with favorable pharmacokinetic characteristics for CNS penetration: teniposide, omacetaxine mepesuccinate, and marizomib. Conclusions: Our twelve IDH-mutant cell cultures show high similarity to the parental tissues and offer a unique tool to study the biology and drug sensitivities of high-grade IDHmt gliomas in vitro. Our drug screening studies reveal lack of sensitivity to IDHmt inhibitors, but sensitivity to a set of nine available anti-cancer agents.

show abstract

Regorafenib CSF Penetration, Efficacy, and MRI Patterns in Recurrent Malignant Glioma Patients

Cited by 28 publications

References 40 publications

Generation, characterization, and drug sensitivities of 12 patient-derived IDH1-mutant glioma cell cultures

Generation, characterization, and drug sensitivities of 12 patient-derived IDH1-mutant glioma cell cultures

Preliminary results using PET/MR in glioblastoma patients treated with regorafenib: an 18F-FET and DWI-ADC comparison

Generation, characterization and drug sensitivities of twelve patient-derived IDH1 mutant glioma cell cultures

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