Effects of targeting the VEGF and PDGF pathways in diffuse orthotopic glioma models

Abstract

Currently available compounds that interfere with VEGF-A signalling effectively inhibit angiogenesis in gliomas, but influence diffuse infiltrative growth to a much lesser extent. Development of a functional tumour vascular bed not only involves VEGF-A but also requires platelet-derived growth factor receptor-β (PDGFRβ), which induces maturation of tumour blood vessels. Therefore, we tested whether combined inhibition of VEGFR and PDGFRβ increases therapeutic benefit in the orthotopic glioma xenograft models E98 and E473, both displaying the diffuse infiltrative growth that is characteristically observed in most human gliomas. We used bevacizumab and vandetanib as VEGF(R) inhibitors, and sunitinib to additionally target PDGFRβ. We show that combination therapy of sunitinib and vandetanib does not improve therapeutic efficacy compared to treatment with sunitinib, vandetanib or bevacizumab alone. Furthermore, all compounds induced reduction of vessel leakage in compact E98 tumour areas, resulting in decreased detectability of these mostly infiltrative xenografts in Gd-DTPA-enhanced MRI scans. These data show that inhibition of VEGF signalling cannot be optimized by additional PDGFR inhibition and support the concept that diffuse infiltrative areas in gliomas are resistant to anti-angiogenic therapy.

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models

“…The differences in VEGF expression of the tumors in distinct locations originating from the same cell line confirm that the orthotopic microenvironment and the resulting growth pattern significantly influence gene expression in glioma cells, a phenomenon that has been described previously (19,20). Moreover, it has been shown that in glioblastoma, VEGF is predominantly overexpressed in hypoxic, perinecrotic cells (35,36). Indeed, in our study, the VEGF expression in subcutaneous E98FM tumors was especially present around areas of necrosis, whereas in intracranial E98FM tumors, necrosis and VEGF expression were lacking and this also coincided with lack of bevacizumab uptake studied ex vivo and by PET.…”

“…Also in DIPG, decreased phosphoVEGR2 levels in peripheral blood mononuclear cells (PBMC) did not correlate with treatment response (15). In the E98 xenograft model used in this study, treatment with bevacizumab did not increase survival, nor did it influence the growth pattern in the diffusely growing parts of the tumor (36). This suggest simply decreasing VEGF in the blood pool is, at least for the tumor types studied and our xenograft model, often insufficient for adequate tumor targeting and instead, local bevacizumab accumulation seems needed (47)(48)(49).…”

Intracellular and extracellular domains of protein tyrosine phosphatase PTPRZ-B differentially regulate glioma cell growth and motility

“…Athymic female BALB/c nu/nu mice (18–25 gram, age 6–8 weeks) were kept under specified pathogen-free conditions and received food and water ad libitum . E98 and E434 cells were grown as spheroids in supplemented neurobasal medium for at least two weeks prior to orthotopic injection [29]. A 20 μL cell suspension (10 7 cells/mL in PBS) containing a mixture of shSCR/GFP and shPTPRZ1/TagRFP labeled cells was injected per animal (n=5 and 4 for E98 and E434 cells, respectively).…”

Stratification of 18F-Labeled PET Imaging Agents for the Assessment of Antiangiogenic Therapy Responses in Tumors

“…Various methods are used clinically to assess antiangiogenic therapies in tumors; these methods include measuring blood flow and blood volume (dynamic contrast-enhanced CT and MR imaging), which assess the downstream effects of angiogenesis (24)(25)(26). However, PET imaging has the ability to directly measure processes in the angiogenesis pathway and potentially provide a more specific means to assess antiangiogenic therapy efficacy in tumors.…”