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New Molecular Targets for the Treatment of Medulloblastoma 4950

Wyatt Ramey and M.Yashar S. Kalani

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Medulloblastoma remains the most common malignant pediatricbrain tumor. Despite high survival rates associated with treatment,conventional regimens possess several serious morbidities. Conse-quently, the need for safer treatment alternatives with fewer long-term sequelae has prompted investigation into inhibition of specificfactors that promote tumor survival and growth.In a recent set of elegant experiments, Snuderl et al. examined

placental growth factor (PlGF) and neuropilin 1 (Nrp1), which act inconcert to foster medulloblastoma growth and spread, as potentialtargets of antitumor therapy (1). Because PlGF expression was not

Figure 1. Inhibition of placental growth factor (PlGF) leads to reof D283-MED tumors transfected with GLuc. We initiated treproduced clinical symptoms and were apparent by whole-boddrop metastases were observed at 3 weeks (arrows). At 6 weethe cerebellum (red arrowheads) and spine (red arrows), whereboth the cerebellum (yellow arrowheads) and spine (yellow ar

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limited to any particular genetic subtype of medulloblastoma, inhi-bition of PlGF (Figure 1) can be used as an alternative to standardregimens. PlGF acts by stimulating vital growth factors via themitogen-activated protein kinase (MAPK) cascade, an action medi-ated by its receptor Nrp1. Nrp1 is essential to PlGF function andrepresents a poor prognosticator when overexpressed in medullo-blastoma. Sonic hedgehog (Shh) secreted by tumor cells acts viaparacrine signaling to trigger stromal release of PlGF, a conceptpreviously unknown in this cancer’s pathophysiology that potentialsa novel site for therapeutic development. It is therefore not surprising

gression of medulloblastoma. (A) Whole-body imagingQ1atment 3 weeks after implantation, when tumors

y imaging (arrowheads). Additionally, small spinal cordks, IgG-treated control tumors have progressed both inas aPlGF [R] (TB403)-treated tumors have regressed inrows). (continues)

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News items of interest may be forwarded to:Felipe C. Albuquerque, M.D.Section Editor, WORLD NEUROSURGERY NewsE-mail: Felipe.albuquerque@bnaneuro.net

Felipe C. Albuquerque, M.D.Section Editor,

WORLD NEUROSURGERY News

Issam Awad, M.D.Section Editor,

WORLD NEUROSURGERY News

that inhibition of Shh results in decreased tumor growth andincreased survival, likely due to its interaction with PlGF but alsopossibly due to cross-talk with other pathways.

Figure 1. (continued) (B) Blood GLucmeasurement is amarker of3 weeks (D283-MED) or 4 weeks (D341-MED) after implantatia significant decrease in total tumor burden (*P < 0.001 at endSEM. (C) Survival was significantly increased in both orthotopicgroup). TheD283model was treatedwith both the Roche antibo(aPlGF [G]). TheD341modelwas treatedwith TB-403.AllaPlGFno clinical symptoms. (D, E) Murine-specific anti-PlGF Ab 5D11spontaneous model of medulloblastoma. (D) At the endpoint osymptoms, such as hunched posture, and had preserved bodydecreased tumor size (measured in cross-section, **P ¼ 0.047corresponding controls, respectively; n ¼ 8/group, 2 separate ewere treatedwith themurine-specific antibody 5D11D4 (amPlGbars represent SEM. (From: Snuderl M, Batista A, Kirkpatrick N1 pathway inhibits growth and spread of medulloblastoma. Ce

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For the first time, Snuderl et al. demonstrate the intricacies ofthe PlGF/Nrp1 axis in relation to medulloblastoma and its positiveeffects on tumor spread and growth. Knowing these 2 molecules

total tumor burden. aPlGF [R] (TB403) therapy is initiatedon of medulloblastoma tumors. Treated tumors showed

Q2point, n ¼ 10/group, mean � SEM). Error bars representmodels with anti-PlGF inhibition (**P < 0.0001, n ¼ 10/dy TB403 (aPlGF [R]) and the Genentech antibody C9.V2[R]-treatedmice that survived at theendof study showedD4 (amPlGF) shows similar effect in Smo/Smof the study, amPlGF-treated animals showed no clinicalweight (**P ¼ 0.0044, n ¼ 8/group) and (E) significantand P ¼ 0.01, amPlGF and aPlGF as compared toxperiments, animals randomized by age and sex). MiceF) or the Genentech anti-PlGF antibody (aPlGF [G]). ErrorD, et al: Targeting placental growth factor/neuropilinll 152:1065-1076, 2013.)

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collectively act to sustain tumor survival, new therapies may bedirected at inhibition of these factors or some downstreamproduct. Although inhibition of PlGF and Nrp1 resulted in

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substantial tumor regression and improved survival, it never led tocomplete tumor obliteration, indicating the presence of a yetunknown resistance mechanism.

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REFERENCE

1. Snuderl M, Batista A, Kirkpatrick ND, Ruiz deAlmodovar C, Riedemann L, Walsh EC, Anolik R,Huang Y, Martin JD, Kamoun W, Knevels E,Schmidt T, Farrar CT, Vakoc BJ, Mohan N, Chung E,Roberge S, Peterson T, Bais C, Zhelyazkova BH, Yip S,

Hasselblatt M, Rossig C, Niemeyer E, Ferrara N,Klagsbrun M, Duda DG, Fukumura D, Xu L,Carmeliet P, Jain RK: Targeting placental growthfactor/neuropilin 1 pathway inhibits growth andspread of medulloblastoma. Cell 152:1065-1076, 2013.

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Division of Neurological Surgery, BarrowNeurological Institute, Phoenix, Arizona, USA

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1878-8750/$ - see front matter ª 2013 Elsevier Inc.All rights reserved.http://dx.doi.org/10.1016/j.wneu.2013.05.006

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