Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors
Gabriele Bergers, … , Emily Bergsland, Douglas Hanahan
Gabriele Bergers, … , Emily Bergsland, Douglas Hanahan
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1287-1295. https://doi.org/10.1172/JCI17929.
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Article Oncology

Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors

Abstract

Functions of receptor tyrosine kinases implicated in angiogenesis were pharmacologically impaired in a mouse model of pancreatic islet cancer. An inhibitor targeting VEGFRs in endothelial cells (SU5416) is effective against early-stage angiogenic lesions, but not large, well-vascularized tumors. In contrast, a kinase inhibitor incorporating selectivity for PDGFRs (SU6668) is shown to block further growth of end-stage tumors, eliciting detachment of pericytes and disruption of tumor vascularity. Importantly, PDGFRs were expressed only in perivascular cells of this tumor type, suggesting that PDGFR+ pericytes in tumors present a complimentary target to endothelial cells for efficacious antiangiogenic therapy. Therapeutic regimes combining the two kinase inhibitors (SU5416 and SU6668) were more efficacious against all stages of islet carcinogenesis than either single agent. Combination of the VEGFR inhibitor with another distinctive kinase inhibitor targeting PDGFR activity (Gleevec) was also able to regress late-stage tumors. Thus, combinatorial targeting of receptor tyrosine kinases shows promise for treating multiple stages in tumorigenesis, most notably the often-intractable late-stage solid tumor.

Authors

Gabriele Bergers, Steven Song, Nicole Meyer-Morse, Emily Bergsland, Douglas Hanahan

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Improved efficacy at all stages of islet carcinogenesis produced by comb...
Improved efficacy at all stages of islet carcinogenesis produced by combining the VEGFR-inhibitor SU5416 with SU6668 or Gleevec, two drugs that inhibit PDGFR signaling. Mice were injected subcutaneously with 50–75 mg/kg SU5416 twice a week and in addition received either daily oral administration of 200 mg/kg SU6668 or twice daily dosing of 50 mg/kg Gleevec (STI571). (The dosage of SU5416 had to be reduced from that used in the single-agent trials shown in Figure 1 due to SU5416-specific toxic side effects.) The average number of angiogenic islets ± SEM at 10.5 weeks in control and treated mice are shown in the prevention trial. The average tumor burden ± SEM of PBS/vehicle–treated mice is indicated at 10, 12, and 13.5 weeks, for comparison with SU5416 + SU6668–treated mice at 13.5 and 16 weeks, and with SU5416 + Gleevec–treated mice at 16 weeks. Tumor burdens were assessed as described in Methods. Statistical analysis was performed with a two-tailed, unpaired Mann-Whitney test comparing experimental groups with PBS-injected control mice. Tumor burdens of experimental groups in the regression trial were compared with that of 12-week-old Rip1Tag2 mice. Cohorts of 6–21 animals were used. P values less than 0.1 are considered statistically significant. (P values of SU5416 + SU6668 PT = 0.0002, SU5416 + SU6668 IT = 0.0008, SU5416 + SU6668 RT = 0.0003, and SU5416 + Gleevec RT = 0.0007.