Preclinical evaluation of sunitinib, a multi-tyrosine kinase inhibitor, as a radiosensitizer for human prostate cancer

Abstract

BackgroundMany prostate cancers demonstrate an increased expression of growth factor receptors such as vascular endothelial growth factor receptor (VEGFR) and platelet derived growth factor receptor (PDGFR) which have been correlated with increased resistance to radiotherapy and poor prognosis in other tumors. Therefore, response to radiation could potentially be improved by using inhibitors of these abnormally activated pathways. We have investigated the radiosensitizing effects of sunitinib, a potent, multi-tyrosine kinase inhibitor of the VEGFR and PDGFR receptors, on human prostate cancer cells.MethodsThe radiosensitizing effects of sunitinib were assessed on human prostate cancer cell lines DU145, PC3 and LNCaP by clonogenic assay. Sunitinib’s ability to inhibit the activities of its key targets was determined by immunoblot analysis. The radiosensitizing effects of sunitinib in vivo were tested on human tumor xenografts growing in nude mice where response was assessed by tumor growth delay.ResultsClonogenic survival curve assays for both DU145 and PC3 cells showed that the surviving fraction at 2 Gy was reduced from 0.70 and 0.52 in controls to 0.44 and 0.38, respectively, by a 24 hr pretreatment with 100 nM sunitinib. LNCaP cells were not radiosensitized by sunitinib. Dose dependent decreases in VEGFR and PDGFR activation were also observed following sunitinib in both DU145 and PC3 cells. We assessed the ability of sunitinib to radiosensitize PC3 xenograft tumors growing in the hind limb of nude mice. Sunitinib given concurrently with radiation did not prolong tumor growth delay. However, when animals were treated with sunitinib commencing the day after fractionated radiation was complete, tumor growth delay was enhanced compared to radiation alone.ConclusionsWe conclude, based on the in vivo results, that sunitinib and radiation do not interact directly to radiosensitize the PC3 tumor cells in vivo as they did in vitro. The fact that tumor growth delay was enhanced when sunitinib was given after radiotherapy was completed suggests that sunitinib may be acting on the irradiated tumor stroma and suppressing its ability to sustain regrowth of the irradiated tumor. Based on these preclinical findings, we suggest that the combination of sunitinib and radiation for the treatment of prostate cancer deserves further development.

Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy

“…In a preclinical evaluation of sunitinib as a radiosensitizer for human prostate cancer, Brooks and colleagues concluded that sunitinib and radiation therapy do not interact directly to radiosensitize PC3 tumor cells in vivo (22). However, the fact that there was additional delay in tumor growth suggested that sunitinib may be acting on the tumor stroma by suppressing its ability to sustain regrowth from the irradiated tumor.…”

Emerging roles of PDGF-D in EMT progression during tumorigenesis

“…However, to our knowledge, small chemical inhibitors of PDGF-D have not been developed so far with proven anti-tumor efficacy in humans. Because PDGF-D exerts its function via activation of its receptor PDGFR-β, multiple small molecule tyrosine kinase inhibitors that inactivate PDGFR have been reported 102–105 . For example, imatinib, a tyrosine kinase inhibitor that interferes with the phosphorylation and activation of PDGFRβ, has been reported to inhibit cell growth and invasion in various cancer cell lines 106 .…”

“…Sunitinib, a multi-tyrosine kinase inhibitor, reduces survival and migration of human meningioma cells by targeting PDGFR 107 . Moreover, Sunitinib could serve as radiosensitizer for human prostate cancer partly through the inhibition of PDGFR and VEGFR 102 . ABT-348 exerts its anti-tumor activity via targeting the VEGFR, PDGFR, Aurora, and SRC kinase 103 .…”

Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

“…Sunitinib is an orally bioavailable multi-tyrosine kinase receptor inhibitor with potent activity against VEGFR and PDGFR that has demonstrated enhanced efficacy of radiation therapy in experimental pre-clinical models [10–11]. Combined PDGFR and VEGFR inhibitor therapy facilitated optimal antiangiogenic and antiproliferative effects of radiation in prostate cancer and glioma models compared to either inhibitor alone [12].…”