PMID- 32140451
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 10
DP  - 2020
TI  - Role of mTOR and VEGFR Inhibition in Prevention of Metastatic Tumor Growth in the 
      Spine.
PG  - 174
LID - 10.3389/fonc.2020.00174 [doi]
LID - 174
AB  - Objective: Spinal metastatic disease remains a major problem of oncological 
      diseases. Patients affected may suffer pain, spinal instability, and severe 
      neurological deficits. Today, palliative surgery and radiotherapy are the 
      mainstays of therapy. In contrast, preventive treatment strategies or treatment 
      concepts for an early stage are lacking. Here, we have used a syngeneic, 
      experimental spine metastases model in the mouse to test the efficacy of mTOR 
      inhibition and anti-angiogenesis on the formation and progression of spinal 
      melanoma metastases. Methods: We used our previously established syngeneic spinal 
      metastases mouse model by injecting luciferin-transfected B16 melanoma cells into 
      the common carotid artery. Following injection, mice were treated with 
      everolimus, an inhibitor of the mammalian target of rapamycin (mTOR) complex, 
      axitinib, a tyrosine kinase inhibitor, that blocks vascular endothelial growth 
      factor receptors (VEGFR) 1-3, as well as placebo. Animals were followed-up daily 
      by neurological assessment and by repeat in vivo bioluminescence imaging. With 
      occurrence of neurological deficits, a spinal MRI was performed, and mice were 
      sacrificed. The whole spine was dissected free and analyzed by 
      immunohistochemical techniques. Results: Overall survival was 23 days in the 
      control group, significantly prolonged to 30 days (p = 0.04) in the everolimus 
      group, and to 28 days (p = 0.04) in the axitinib group. While 78% of mice in the 
      placebo group developed symptomatic metastatic epidural spinal cord compression, 
      only 50% did so in the treatment groups. The mean time to manifestation of 
      paralysis was 22 days in the control group, 26 days (p = 0.10) in the everolimus 
      group, and 27 days (p = 0.06) in the axitinib group. Screening for spinal 
      metastases by bioluminescence imaging on two different time points showed a 
      decrease in metastatic tumor formation in the treatment groups compared to the 
      controls. Immunohistochemical analysis confirmed the bioactivity of the two 
      compounds: The Ki67 proliferation labeling index was reduced in the everolimus 
      group and numbers of CD31 positive endothelial cells were reduced in the axitinib 
      group. Conclusion: Both, the mTOR inhibitor everolimus as well as 
      antiangiogenetic effects by the VEGFR inhibitor axitinib showed potential to 
      prevent and retard formation of symptomatic spinal metastases. However, the 
      therapeutic efficacy was only mild in this experimental model.
CI  - Copyright (c) 2020 Kratzsch, Piffko, Broggini, Czabanka and Vajkoczy.
FAU - Kratzsch, Tobias
AU  - Kratzsch T
AD  - Department of Neurosurgery, Charite University Hospital, Berlin, Germany.
FAU - Piffko, Andras
AU  - Piffko A
AD  - Department of Neurosurgery, Charite University Hospital, Berlin, Germany.
FAU - Broggini, Thomas
AU  - Broggini T
AD  - Department of Physics, University of California, San Diego, La Jolla, CA, United 
      States.
FAU - Czabanka, Marcus
AU  - Czabanka M
AD  - Department of Neurosurgery, Charite University Hospital, Berlin, Germany.
FAU - Vajkoczy, Peter
AU  - Vajkoczy P
AD  - Department of Neurosurgery, Charite University Hospital, Berlin, Germany.
LA  - eng
PT  - Journal Article
DEP - 20200219
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC7042460
OTO - NOTNLM
OT  - axitinib
OT  - everolimus
OT  - preclinical mouse model
OT  - spinal metastases
OT  - targeted therapy
EDAT- 2020/03/07 06:00
MHDA- 2020/03/07 06:01
PMCR- 2020/01/01
CRDT- 2020/03/07 06:00
PHST- 2019/11/17 00:00 [received]
PHST- 2020/01/31 00:00 [accepted]
PHST- 2020/03/07 06:00 [entrez]
PHST- 2020/03/07 06:00 [pubmed]
PHST- 2020/03/07 06:01 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2020.00174 [doi]
PST - epublish
SO  - Front Oncol. 2020 Feb 19;10:174. doi: 10.3389/fonc.2020.00174. eCollection 2020.