Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

Mayr, Lisa; Guntner, Armin Sebastian; Madlener, Sibylle; Schmook, Maria Theresa; Peyrl, Andreas; Azizi, Amedeo A.; Dieckmann, Karin; Reisinger, Dominik; Stepien, Natalia; Schramm, Kathrin; Laemmerer, Anna; Jones, David; Ecker, Jonas; Sahm, Felix; Milde, Till; Pajtler, Kristian W.; Blattner-Johnson, Mirjam; Strbac, Miroslav; Dorfer, Christian; Czech, Thomas; Kirchhofer, Dominik; Gabler, Lisa; Berger, Walter; Haberler, Christine; Müllauer, Leonhard; Buchberger, Wolfgang; Slavc, Irene; Lötsch-Gojo, Daniela; Gojo, Johannes

doi:10.3390/jpm10040290

Cited by 23 publications

(26 citation statements)

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“…These analyses demonstrated the overall remarkable sensitivity of EPN towards various FGFRis with IC 50 s in the low-micromolar to nanomolar range. In general, the IC 50 values of FGFRis were comparable to FGFR-driven control models [ 14 ] but also to other RTK-driven pediatric brain cancer cell models including NTRK fusion-driven HGG cell models towards NTRK-inhibitors [ 9 , 39 ]. High sensitivity was observed not only for the multi-RTKi ponatinib, but also the more FGFR-specific AZD-4547 inhibitor, proving FGFRs as central therapeutic targets in EPN cells.…”

Section: Discussionmentioning

confidence: 88%

Targeting fibroblast growth factor receptors to combat aggressive ependymoma

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 88%

Targeting fibroblast growth factor receptors to combat aggressive ependymoma

et al. 2021

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“…Mutations concerning either BRAF or NTRK fusions are of particular interest since they represent potentially targetable alterations. Data concerning inhibition has been encouraging in BRAF V600E mutant gliomas [ 89 ] as well as entrectinib in NTRK -fusion positive pHGG [ 90 ].…”

Section: Resultsmentioning

confidence: 99%

TERT Promoter Alterations in Glioblastoma: A Systematic Review

Olympios¹,

Gilard

Marguet

et al. 2021

Cancers

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Glioblastoma, the most frequent and aggressive primary malignant tumor, often presents with alterations in the telomerase reverse transcriptase promoter. Telomerase is responsible for the maintenance of telomere length to avoid cell death. Telomere lengthening is required for cancer cell survival and has led to the investigation of telomerase activity as a potential mechanism that enables cancer growth. The aim of this systematic review is to provide an overview of the available data concerning TERT alterations and glioblastoma in terms of incidence, physiopathological understanding, and potential therapeutic implications.

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“…However, Phase I studies for melanoma showed considerable side effects of this drug combination, which limited the drug exposure [ 66 , 68 ]. In our experience with combination of targeted treatment, also including everolimus and trametinib, the side effects were manageable for a certain period in pediatric patients, but combination therapy had to be discontinued eventually due to skin toxicity [ 69 ]. Nevertheless, we initiated this combination of treatment in the reported case, due to urgent clinical need.…”

Section: Discussionmentioning

confidence: 99%

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis

Baumgartner

Stepien

Mayr

et al. 2021

JPM

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Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of NRAS (n = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type.

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Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma

Cited by 23 publications

References 50 publications

Targeting fibroblast growth factor receptors to combat aggressive ependymoma

Targeting fibroblast growth factor receptors to combat aggressive ependymoma

TERT Promoter Alterations in Glioblastoma: A Systematic Review

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis

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