Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 29, Pages 10185-10190Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0803194105
Keywords
combination therapy; pericytes
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Funding
- NCI NIH HHS [1 R01CA95654-01, R01 CA082923, CA082923, R01 CA095654] Funding Source: Medline
- NHLBI NIH HHS [HL 59157, P01 HL024136, HL074267, R01 HL074267, HL-24136, R01 HL059157] Funding Source: Medline
- NINDS NIH HHS [R01 NS052830, NS052830] Funding Source: Medline
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The simultaneous targeting of both endothelial cells and pericytes via inhibition of VEGF receptor (VEGFR) and PDGF beta receptor (PDGFR beta) signaling, respectively, has been proposed to enhance the efficacy of antiangiogenic tumor therapy. Clinical and preclinical modeling of combined VEGFR and PDGFR beta signaling inhibition, however, has used small molecule kinase inhibitors with inherently broad substrate specificities, precluding detailed examination of this hypothesis. Here, adenoviral expression of a soluble VEGFR2/Flk1 ectodomain (Ad Flk1-Fc) in combination with a soluble ectodomain of PDGFR beta (Ad sPDGFR beta) allowed highly selective inhibition of these pathways. The activity of Ad sPDGFR beta was validated in vitro against PDGF-BB and in vivo with near-complete blockade of pericyte recruitment in the angiogenic corpus luteum, resulting in prominent hemorrhage, thus demonstrating an essential function for PDGF signaling during ovarian angiogenesis. Combination therapy with Ad PDGFR beta and submaximal doses of Ad Flk1-Fc produced modest additive antitumor effects; however, no additivity was observed with maximal VEGF inhibition in numerous s.c. models. Notably, VEGF inhibition via Ad Flk1-Fc was sufficient to strongly suppress tumor endothelial and pericyte content as well as intratumoral PDGF-B mRNA, obscuring additive Ad sPDGFR beta effects on pericytes or tumor volume. These studies using highly specific soluble receptors suggest that additivity between VEGFR and PDGFR beta inhibition depends on the strength of VEGF blockade and appears minimal under conditions of maximal VEGF antagonism.
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