Pazopanib radio-sensitization of human sarcoma tumors Journal Article

   


Authors: Wang, F.; Li, H.; Markovsky, E.; Glass, R.; de Stanchina, E.; Powell, S. N.; Schwartz, G. K.; Haimovitz-Friedman, A.
Article Title: Pazopanib radio-sensitization of human sarcoma tumors
Abstract: Recent data in our laboratory indicate that engagement of host-derived microenvironmental elements impact tumor response to single high dose radiation therapy (SDRT). In these studies we showed that microvascular endothelial damage plays a critical role in tumor response as regulator of direct lethal damage of SDRT. Using a genetic model of Acid Sphingomyelinase (ASMase)-deficient mice we showed that activation of this enzyme by SDRT-induced damage in the endothelium is mandatory for tumor cure. ASMase activation triggers ceramide-mediated apoptosis, and therein microvascular dysfunction, which increased the vulnerability of tumor cells to lethal damage by radiation. Angiogenic factors repressed this activity while a monoclonal antibody targeting VEGF, de-repressed ASMase activity and radiosensitized tumor endothelium when delivered immediately prior to SDRT. In this study, we tested the effect of SDRT in combination with the short-acting anti-angiogenic agent, Pazopanib (anti-VEGFR-1/2/3, PDGF-α/β and c-kit), in two xenograft models of human sarcoma. Pre-treatment with a single dose of Pazopanib increased SDRTinduced ASMase activity and endothelial dysfunction in vitro and in vivo, enhancing SDRT tumor cure, and exhibiting critical dependence on timing relative to SDRT exposure, suggesting a mechanism of action identical to that demonstrated for anti- VEGF/VEGFR2 antibodies. These results demonstrate the ability of Pazopanib to shift the response towards tumor cure and could therefore have a significant impact on clinical trial development in combination with SDRT for sarcoma cancer patients. © Wang et al.
Keywords: vasculotropin; controlled study; nonhuman; mouse; animal tissue; apoptosis; radiotherapy; animal experiment; animal model; in vivo study; in vitro study; tumor xenograft; enzyme activity; sarcoma; endothelium cell; fibroblast growth factor 2; tumor cell; pazopanib; single drug dose; radiosensitization; endothelial dysfunction; ceramide; sphingomyelin phosphodiesterase; mouse model; tumor angiogenesis; tumor blood flow; article; sarcoma cell line; jj012 cell line; single high dose radiation therapy (sdrt); mpnst3 cell line; single high dose radiation therapy
Journal Title: Oncotarget
Volume: 9
Issue: 10
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2018-02-06
Start Page: 9311
End Page: 9324
Language: English
DOI: 10.18632/oncotarget.24281
PROVIDER: scopus
PMCID: PMC5823639
PUBMED: 29507692
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85041388754&doi=10.18632%2foncotarget.24281&partnerID=40&md5=2154e6b8026e085f2e17f4e5953356db
Notes: Article -- Export Date: 1 March 2018 -- Source: Scopus
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MSK Authors
  1. Simon Nicholas Powell
    331 Powell
  2. Adriana Haimovitz-Friedman
    170 Haimovitz-Friedman
  3. Elisa De Stanchina
    343 De Stanchina
  4. Feng Wang
    3 Wang
  5. Hongyan Li
    11 Li
  6. Ela Markovsky
    6 Markovsky
  7. Ryan Eric Glass
    3 Glass
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