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UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts

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Abstract

Background

Group 3 tumors account for approximately 25–30% of medulloblastomas and have the worst prognosis. UAB30 is a novel synthetic rexinoid shown to have limited toxicities in humans and significant efficacy in the pediatric neuroectodermal tumor, neuroblastoma. We hypothesized that treatment with UAB30 would decrease tumorigenicity in medulloblastoma patient-derived xenografts (PDXs).

Methods

Three group 3 medulloblastoma PDXs (D341, D384 and D425) were utilized. Cell viability, proliferation, migration and invasion assays were performed after treatment with UAB30 or 13-cis-retinoic acid (RA). Cell cycle analysis was completed using flow cytometry. A flank model, a cerebellar model, and a model of leptomeningeal metastasis using human medulloblastoma PDX cells was used to assess the in vivo effects of UAB30 and RA.

Results

UAB30 treatment led to cell differentiation and decreased medulloblastoma PDX cell viability, proliferation, migration and invasion and G1 cell cycle arrest in all three PDXs similar to RA. UAB30 and RA treatment of mice bearing medulloblastoma PDX tumors resulted in a significant decrease in tumor growth and metastasis compared to vehicle treated animals.

Conclusions

UAB30 decreased viability, proliferation, and motility in group 3 medulloblastoma PDX cells and significantly decreased tumor growth in vivo in a fashion similar to RA, suggesting that further investigations into the potential therapeutic application of UAB30 for medulloblastoma are warranted.

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Acknowledgements

Funding provided by the University of Alabama, Birmingham, Comprehensive Cancer Center to G.K.F. and E.A.B. National Institutes of Health (T32 CA091078 to E.F.G. and L.L.S.) (T32 CA183926 to A.P.W.) and (P30 AR048311 and P30 AI27667 to the University of Alabama Flow Cytometry Core).

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Authors and Affiliations

  1. Division of Pediatric Surgery, Department of Surgery, University of Alabama, Birmingham, Birmingham, AL, USA

    Evan F. Garner, Laura L. Stafman, Adele P. Williams, Caroline Goolsby, Jerry E. Stewart & Elizabeth A. Beierle

  2. Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama, Birmingham, Birmingham, AL, USA

    Jamie M. Aye, Blake P. Moore, Li Nan & Gregory K. Friedman

  3. Department of Dermatology, University of Alabama, Birmingham, Birmingham, AL, USA

    Venkatram R. Atigadda

  4. Department of Cell, Developmental and Integrative Biology, University of Alabama, Birmingham, Birmingham, AL, USA

    Anita B. Hjelmeland

  5. Birmingham, USA

    Elizabeth A. Beierle

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  1. Evan F. Garner
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Contributions

All authors contributed to the manuscript and have approved the final version. Details include: EFG experimental design, data acquisition, analysis and interpretation of the data, manuscript revision; LLS data acquisition, manuscript revision; APW data acquisition, manuscript revision; JMA data acquisition, manuscript revision; CG data analysis, manuscript revision; VRA experimental design and reagents, manuscript revision; BPM data acquisition, manuscript revision; NL data analysis, manuscript revision; JES data acquisition, data analysis, manuscript revision; ABH experimental design and reagents, manuscript revision; GFK experimental design, manuscript revision; EAB experimental design, data analysis and interpretation, writing manuscript, manuscript revision.

Corresponding author

Correspondence to Elizabeth A. Beierle.

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The authors declare that they have no conflicts of interest.

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All applicable international, national, and /or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. The University of Alabama, Birmingham Institutional Animal Care and Use Committee approved all animal experiments (IACUC-09355, IACUC-10299). This article does not contain any studies with human participants performed by any of the authors.

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Garner, E.F., Stafman, L.L., Williams, A.P. et al. UAB30, a novel RXR agonist, decreases tumorigenesis and leptomeningeal disease in group 3 medulloblastoma patient-derived xenografts. J Neurooncol 140, 209–224 (2018). https://doi.org/10.1007/s11060-018-2950-1

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