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Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

Publication ,  Journal Article
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; Mclendon, R; Ali-Osman, F; Bigner, DD ...
Published in: Journal of neurochemistry
June 2015

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

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Published In

Journal of neurochemistry

DOI

EISSN

1471-4159

ISSN

0022-3042

Publication Date

June 2015

Volume

133

Issue

5

Start / End Page

730 / 738

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Proteomics
  • Phosphorylation
  • Neurology & Neurosurgery
  • Middle Aged
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Humans
 

Citation

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Brown, K. E., Chagoya, G., Kwatra, S. G., Yen, T., Keir, S. T., Cooter, M., … Kwatra, M. M. (2015). Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development. Journal of Neurochemistry, 133(5), 730–738. https://doi.org/10.1111/jnc.13032
Brown, Kristine E., Gustavo Chagoya, Shawn G. Kwatra, Timothy Yen, Stephen T. Keir, Mary Cooter, Katherine A. Hoadley, et al. “Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.Journal of Neurochemistry 133, no. 5 (June 2015): 730–38. https://doi.org/10.1111/jnc.13032.
Brown KE, Chagoya G, Kwatra SG, Yen T, Keir ST, Cooter M, et al. Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development. Journal of neurochemistry. 2015 Jun;133(5):730–8.
Brown, Kristine E., et al. “Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.Journal of Neurochemistry, vol. 133, no. 5, June 2015, pp. 730–38. Epmc, doi:10.1111/jnc.13032.
Brown KE, Chagoya G, Kwatra SG, Yen T, Keir ST, Cooter M, Hoadley KA, Rasheed A, Lipp ES, Mclendon R, Ali-Osman F, Bigner DD, Sampson JH, Kwatra MM. Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development. Journal of neurochemistry. 2015 Jun;133(5):730–738.
Journal cover image

Published In

Journal of neurochemistry

DOI

EISSN

1471-4159

ISSN

0022-3042

Publication Date

June 2015

Volume

133

Issue

5

Start / End Page

730 / 738

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Proteomics
  • Phosphorylation
  • Neurology & Neurosurgery
  • Middle Aged
  • Mice, Nude
  • Mice, Inbred BALB C
  • Mice
  • Male
  • Humans