2. Academic Validation
  3. Inhibition of Farnesyltransferase Potentiates NOTCH-Targeted Therapy against Glioblastoma Stem Cells

Inhibition of Farnesyltransferase Potentiates NOTCH-Targeted Therapy against Glioblastoma Stem Cells

  • Stem Cell Reports. 2017 Dec 12;9(6):1948-1960. doi: 10.1016/j.stemcr.2017.10.028.
Yufang Ma 1,  Zhixiang Cheng 2,  Jing Liu 3,  Luke Torre-Healy 4,  Justin D Lathia 4,  Ichiro Nakano 5,  Yan Guo 6,  Reid C Thompson 7,  Michael L Freeman 8,  Jialiang Wang 9
Affiliations

Affiliations

  • 1 College of Pharmacy, Belmont University, Nashville, TN 37212, USA.
  • 2 Department of Pain Management, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210011, China.
  • 3 Department of Neurosurgery, Shengjing Hospital, China Medical University, Shenyang 110004, China.
  • 4 Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
  • 5 Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 6 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 7 Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 8 Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 9 Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: [email protected].
PMID: 29198824 DOI: 10.1016/j.stemcr.2017.10.028
Abstract

Accumulating evidence suggests that Cancer cells with stem cell-like phenotypes drive disease progression and therapeutic resistance in glioblastoma (GBM). Notch regulates self-renewal and resistance to chemoradiotherapy in GBM stem cells. However, NOTCH-targeted γ-secretase inhibitors (GSIs) exhibited limited efficacy in GBM patients. We found that farnesyltransferase inhibitors (FTIs) significantly improved sensitivity to GSIs. This combination showed significant antineoplastic and radiosensitizing activities in GBM stem cells, whereas non-stem GBM cells were resistant. These combinatorial effects were mediated, at least partially, through inhibition of Akt and cell-cycle progression. Using subcutaneous and orthotopic GBM models, we showed that the combination of FTIs and GSIs, but not either agent alone, significantly reduced tumor growth. With concurrent radiation, this combination induced a durable response in a subset of orthotopic tumors. These findings collectively suggest that the combination of FTIs and GSIs is a promising therapeutic strategy for GBM through selectively targeting the Cancer stem cell subpopulation.

Keywords

Notch; farnesyltransferase inhibitors; glioblastoma stem cells; γ-secretase inhibitors.

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