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The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion.

Publication ,  Journal Article
Hjelmeland, AB; Lattimore, KP; Fee, BE; Shi, Q; Wickman, S; Keir, ST; Hjelmeland, MD; Batt, D; Bigner, DD; Friedman, HS; Rich, JN
Published in: Mol Cancer Ther
September 2007

Monotherapies have proven largely ineffective for the treatment of glioblastomas, suggesting that increased patient benefit may be achieved by combining therapies. Two protumorigenic pathways known to be active in glioblastoma include RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/target of rapamycin (TOR). We investigated the efficacy of a combination of novel low molecular weight inhibitors LBT613 and RAD001 (everolimus), which were designed to target RAF and TOR, respectively. LBT613 decreased phosphorylation of extracellular signal-regulated kinase 1 and 2, downstream effectors of RAF, in a human glioma cell line. RAD001 resulted in decreased phosphorylation of the TOR effector S6. To determine if targeting RAF and TOR activities could result in decreased protumorigenic glioma cellular behaviors, we evaluated the abilities of LBT613 and RAD001 to affect the proliferation, migration, and invasion of human glioma cells. Treatment with either LBT613 or RAD001 alone significantly decreased the proliferation of multiple human glioma cell lines. Furthermore, LBT613 and RAD001 in combination synergized to decrease glioma cell proliferation in association with G(1) cell cycle arrest. Glioma invasion is a critical contributor to tumor malignancy. The combination of LBT613 and RAD001 inhibited the invasion of human glioma cells through Matrigel to a greater degree than treatment with either drug alone. These data suggest that the combination of LBT613 and RAD001 reduces glioma cell proliferation and invasion and support examination of the combination of RAF and TOR inhibitors for the treatment of human glioblastoma patients.

Duke Scholars

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

September 2007

Volume

6

Issue

9

Start / End Page

2449 / 2457

Location

United States

Related Subject Headings

  • raf Kinases
  • TOR Serine-Threonine Kinases
  • Sirolimus
  • Signal Transduction
  • Proteoglycans
  • Protein Kinases
  • Phosphorylation
  • Phosphoinositide-3 Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mitogen-Activated Protein Kinases
 

Citation

APA
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ICMJE
MLA
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Hjelmeland, A. B., Lattimore, K. P., Fee, B. E., Shi, Q., Wickman, S., Keir, S. T., … Rich, J. N. (2007). The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion. Mol Cancer Ther, 6(9), 2449–2457. https://doi.org/10.1158/1535-7163.MCT-07-0155
Hjelmeland, Anita B., Kathryn P. Lattimore, Brian E. Fee, Qing Shi, Sarah Wickman, Stephen T. Keir, Mark D. Hjelmeland, et al. “The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion.Mol Cancer Ther 6, no. 9 (September 2007): 2449–57. https://doi.org/10.1158/1535-7163.MCT-07-0155.
Hjelmeland AB, Lattimore KP, Fee BE, Shi Q, Wickman S, Keir ST, et al. The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion. Mol Cancer Ther. 2007 Sep;6(9):2449–57.
Hjelmeland, Anita B., et al. “The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion.Mol Cancer Ther, vol. 6, no. 9, Sept. 2007, pp. 2449–57. Pubmed, doi:10.1158/1535-7163.MCT-07-0155.
Hjelmeland AB, Lattimore KP, Fee BE, Shi Q, Wickman S, Keir ST, Hjelmeland MD, Batt D, Bigner DD, Friedman HS, Rich JN. The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion. Mol Cancer Ther. 2007 Sep;6(9):2449–2457.

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

September 2007

Volume

6

Issue

9

Start / End Page

2449 / 2457

Location

United States

Related Subject Headings

  • raf Kinases
  • TOR Serine-Threonine Kinases
  • Sirolimus
  • Signal Transduction
  • Proteoglycans
  • Protein Kinases
  • Phosphorylation
  • Phosphoinositide-3 Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Mitogen-Activated Protein Kinases