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  • Evaluation of Intra-arterial Bevacizumab Delivery on Tumor Growth, Oncogenic Signaling, and Stem Cell Microenvironment in a Human GBM Xenograft

    Final Number:
    517

    Authors:
    Nicholas Berry; Matei A Banu MD; Demirkan B. Gursel PhD; Kartik Kesavabhotla; Casey Tsai; Alejandro Santillan MD; Conor Foley; Jan-karl Burkhardt MD; John A. Boockvar MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2012 Annual Meeting

    Introduction: We used a human GBM xenograft mouse model to compare the effects of intra-arterial(IA) and intra-peritoneal(IP) bevacizumab (BV), a monoclonal antibody to VEGF, on tumor growth and stem cell signaling.

    Methods: U87 GBM cells transduced with the firefly luciferase gene were injected into the left hemisphere of athymic mice, which were subsequently treated with a single dose of IA or IP BV. The IA BV dose was administered via a catheter in the left internal carotid artery and preceded by transient mannitol-mediated osmotic blood brain barrier disruption. Tumor growth was monitored by measuring the tumor’s bioluminescence signal over time. The tumors were removed post-mortem and analyzed with immunohistochemistry and western blot.

    Results: Mice treated with IA BV lived 30% longer than untreated mice and 5% longer than IP treated mice. Similarly, BV slowed tumor growth, with IA BV slowing the increase in luminescence signal more than IP BV. Western blot analysis of these tumors revealed that BV treatment decreased the expression of Akt and VEGF-receptor 2 while also increasing expression of tumor suppressors such as p53 and p27. BV also induced changes in stem cell microenvironment by increasing the level of hypoxia, as demonstrated by increasing HIF1 alpha levels. Immunohistochemical analysis of the tumors showed that more BV was present in the tumor vasculature when it was administered via the IA route.

    Conclusions: IA BV delivery increases survival and decreases tumor growth relative to IP BV delivery and no treatment. These benefits may be related to the fact that more BV is localized to the tumor vasculature when administered via the IA route. BV treatment, independent of delivery method, appears to shift tumor cell signaling away from oncogenic and pro-proliferative pathways. BV also seems to shift the tumor microenvironment towards a more hypoxic millieu.

    Patient Care: Intra-arterial bevacizumab drug delivery combined with blood brain barrier disruption may increase the concentration of the drug that is delivered to the tumor cells, particuarly the perivascular niche in which the tumor stem cells arrive, and decrease systemic side effects, which may, in turn, increase the clinical outcomes associated with bevacizumab therapy.

    Learning Objectives: By the end of this presentation, participants will better understand: (1) the role of tumor stem cells and their microenvironment in tumor biology, (2) the rationale underlying intra-arterial drug delivery and blood brain barrier disruption in the treatment of brain tumors, and (3) the effect of bevacizumab on tumor cells and their microenvironment.

    References:

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