Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma

Donson, Andrew M.; Amani, Vladimir; Warner, Elliot A.; Griesinger, Andrea; Witt, Davis; Levy, Jean M. Mulcahy; Hoffman, Lindsey M.; Hankinson, Todd C.; Handler, Michael H.; Vibhakar, Rajeev; Dorris, Kathleen; Foreman, Nicholas

doi:10.1158/1535-7163.mct-17-1185

Cited by 22 publications

(14 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Utilizing single-cell transcriptomic approaches we could further define undifferentiated subpopulations and differentiation trajectories within EPN tumor tissues [22,23]. In these previous studies, we identified fibroblast growth factor receptor 1 and 3 (FGFR1 and FGFR3) as potential therapeutic targets for EPN [11,23,35]. The mammalian fibroblast growth factor (FGF) family comprises 18 secreted proteins that interact with four different tyrosine kinase FGF receptors (FGFRs) [14].…”

Section: Extended Author Information Available On the Last Page Of The Articlementioning

confidence: 99%

Targeting fibroblast growth factor receptors to combat aggressive ependymoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Extended Author Information Available On the Last Page Of The Articlementioning

confidence: 99%

Targeting fibroblast growth factor receptors to combat aggressive ependymoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…In preclinical ependymoma assays, axitinib, imatinib, and pazopanib have shown promising results [ 99 ], so they may soon jump into clinical trials.…”

Section: Antiangiogenics and Brain Tumorsmentioning

confidence: 99%

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

Ollauri-Ibáñez

Astigarraga

2021

Cancers

View full text Add to dashboard Cite

Cancer is an important cause of death in childhood. In recent years, scientists have made an important effort to achieve greater precision and more personalized treatments against cancer. But since only a few pediatric patients have identifiable therapeutic targets, other ways to stop the neoplastic cell proliferation and dissemination are needed. Therefore, the inhibition of general processes involved in the growth and behavior of tumors can be a relevant strategy for the development of new cancer therapies. In the case of solid tumors, one of these processes is angiogenesis, essential for tumor growth and generation of metastases. This review summarizes the results obtained with the use of antiangiogenic drugs in the main pediatric malignant solid tumors and also an overview of clinical trials currently underway. It should be noted that due to the rarity and heterogeneity of the different types of pediatric cancer, most studies on antiangiogenic drugs include only a small number of patients or isolated clinical cases, so they are not conclusive and further studies are needed.

show abstract

“…Interestingly, a number of the identified compounds have also been identified in previous in vitro compound screens on smaller sets of glial tumors. 41–45 Several of the compounds identified in our screen have also been tested in clinical trials for glioma in the past (see table S5), but none of the compounds were tested specifically in IDH-mutant patients. 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.…”

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

Identification of FDA-Approved Oncology Drugs with Selective Potency in High-Risk Childhood Ependymoma

Cited by 22 publications

References 33 publications

Targeting fibroblast growth factor receptors to combat aggressive ependymoma

Targeting fibroblast growth factor receptors to combat aggressive ependymoma

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

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

Contact Info

Product

Resources

About