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STEM-15. THERAPY-INDUCED CHANGES BY BRAF AND MEK INHIBITORS IN BRAF V600E-MUTATED GLIOMA MODELS PROVIDE POTENTIAL NOVEL THERAPEUTIC OPPORTUNITIES

Publication ,  Journal Article
Park, J; Lancero, H; Nasajpour, E; Garcia, C; Prolo, L; Grant, G; Petritsch, C
Published in: Neuro-Oncology
November 14, 2022

Combinations of the MEK inhibitor trametinib, and BRAF inhibitor dabrafenib (BRAFi+MEKi) show rapid and sustained responses in patients with BRAF V600E-mutated low-grade glioma, but tumor rebound after treatment discontinuation is frequent. Moreover, a lack of response is common in patient with high-grade glioma raising the need for further research into BRAFi+MEKi effects on tumors. We showed previously that BRAF V600E-mutated glioma cells positive for CD133 (Prominin-1), a marker of brain tumor stem cells, show decreased sensitivity to BRAFi, indicative of their role in promoting therapy resistance. BRAF V600E-mutated murine and patient-derived glioma cell lines (STN-10049, SU-aGBM5) were generated and together with established BRAF V600E-mutated cell lines (DBTRG, AM38) were analyzed for changes in gene expression in response to 48 hrs treatment with BRAFi dabrafenib and MEKi trametinib. Cells were analyzed by RNA-seq and gene enrichment analyses while cell culture supernatant was analyzed for cytokine production using an ELISA. Syngeneic, orthotopic BRAF V600E-mutated tumor allograft-bearing mice were treated with BRAFi+MEKi, with therapeutic antibodies against immune checkpoint molecules (anti-PD-L1 and anti-CTLA-4) and with combination of all four agents, and tumors were analyzed by mass cytometry and immunofluorescence for stem and T cell markers. BRAFi+MEKi treatment induced an interferon gamma (IFNg) response gene signature in BRAF V600E-mutated glioma cells and increased HLA gene expression. The frequency of tumor-infiltrating CD4+ CD8+ T cells in syngeneic BRAF V600E-mutated tumor allografts increased with BRAFi+MEKi treatment. Combining BRAFi+MEKi with anti-PD-L1 and anti-CTLA-4 treatment decreased CD133+ cells more effectively than either therapy alone, and resulted in a T cell-dependent survival benefit of mice with orthotopic BRAF V600E-mutated high-grade glioma. Combination of BRAFi+MEKi with immune checkpoint inhibition should be further explored as a viable option to prevent tumor rebound and therapy resistance in patients with BRAF V600E-mutated glioma.

Duke Scholars

Published In

Neuro-Oncology

DOI

EISSN

1523-5866

ISSN

1522-8517

Publication Date

November 14, 2022

Volume

24

Issue

Supplement_7

Start / End Page

vii34 / vii34

Publisher

Oxford University Press (OUP)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1109 Neurosciences
 

Citation

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MLA
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Park, J., Lancero, H., Nasajpour, E., Garcia, C., Prolo, L., Grant, G., & Petritsch, C. (2022). STEM-15. THERAPY-INDUCED CHANGES BY BRAF AND MEK INHIBITORS IN BRAF V600E-MUTATED GLIOMA MODELS PROVIDE POTENTIAL NOVEL THERAPEUTIC OPPORTUNITIES. Neuro-Oncology, 24(Supplement_7), vii34–vii34. https://doi.org/10.1093/neuonc/noac209.132
Park, Jongwhi, Hope Lancero, Emon Nasajpour, Cesar Garcia, Laura Prolo, Gerald Grant, and Claudia Petritsch. “STEM-15. THERAPY-INDUCED CHANGES BY BRAF AND MEK INHIBITORS IN BRAF V600E-MUTATED GLIOMA MODELS PROVIDE POTENTIAL NOVEL THERAPEUTIC OPPORTUNITIES.” Neuro-Oncology 24, no. Supplement_7 (November 14, 2022): vii34–vii34. https://doi.org/10.1093/neuonc/noac209.132.
Park J, Lancero H, Nasajpour E, Garcia C, Prolo L, Grant G, et al. STEM-15. THERAPY-INDUCED CHANGES BY BRAF AND MEK INHIBITORS IN BRAF V600E-MUTATED GLIOMA MODELS PROVIDE POTENTIAL NOVEL THERAPEUTIC OPPORTUNITIES. Neuro-Oncology. 2022 Nov 14;24(Supplement_7):vii34–vii34.
Park, Jongwhi, et al. “STEM-15. THERAPY-INDUCED CHANGES BY BRAF AND MEK INHIBITORS IN BRAF V600E-MUTATED GLIOMA MODELS PROVIDE POTENTIAL NOVEL THERAPEUTIC OPPORTUNITIES.” Neuro-Oncology, vol. 24, no. Supplement_7, Oxford University Press (OUP), Nov. 2022, pp. vii34–vii34. Crossref, doi:10.1093/neuonc/noac209.132.
Park J, Lancero H, Nasajpour E, Garcia C, Prolo L, Grant G, Petritsch C. STEM-15. THERAPY-INDUCED CHANGES BY BRAF AND MEK INHIBITORS IN BRAF V600E-MUTATED GLIOMA MODELS PROVIDE POTENTIAL NOVEL THERAPEUTIC OPPORTUNITIES. Neuro-Oncology. Oxford University Press (OUP); 2022 Nov 14;24(Supplement_7):vii34–vii34.
Journal cover image

Published In

Neuro-Oncology

DOI

EISSN

1523-5866

ISSN

1522-8517

Publication Date

November 14, 2022

Volume

24

Issue

Supplement_7

Start / End Page

vii34 / vii34

Publisher

Oxford University Press (OUP)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1109 Neurosciences