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New Molecular Targets for the Treatment of Medulloblastoma
New Molecular Targets for the Treatment of Medulloblastoma Q3
Wyatt Ramey and M.Yashar S. Kalani
Medulloblastoma remains the most common malignant pediatric brain tumor. Despite high survival rates associated with treatment, conventional regimens possess several serious morbidities. Consequently, the need for safer treatment alternatives with fewer longterm sequelae has prompted investigation into inhibition of specific factors 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 in concert to foster medulloblastoma growth and spread, as potential targets of antitumor therapy (1). Because PlGF expression was not
limited to any particular genetic subtype of medulloblastoma, inhibition of PlGF (Figure 1) can be used as an alternative to standard regimens. PlGF acts by stimulating vital growth factors via the mitogen-activated protein kinase (MAPK) cascade, an action mediated by its receptor Nrp1. Nrp1 is essential to PlGF function and represents a poor prognosticator when overexpressed in medulloblastoma. Sonic hedgehog (Shh) secreted by tumor cells acts via paracrine signaling to trigger stromal release of PlGF, a concept previously unknown in this cancer’s pathophysiology that potentials a novel site for therapeutic development. It is therefore not surprising
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Figure 1. Inhibition of placental growth factor (PlGF) leads to regression of medulloblastoma. (A) Whole-body imaging of D283-MED tumors transfected with GLuc. We initiated treatment 3 weeks after implantation, when tumors produced clinical symptoms and were apparent by whole-body imaging (arrowheads). Additionally, small spinal cord drop metastases were observed at 3 weeks (arrows). At 6 weeks, IgG-treated control tumors have progressed both in the cerebellum (red arrowheads) and spine (red arrows), whereas aPlGF [R] (TB403)-treated tumors have regressed in both the cerebellum (yellow arrowheads) and spine (yellow arrows). (continues)
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- (-): 2-4, - 2013
FLA 5.1.0 DTD WNEU1935_proof 23 May 2013 4:20 pm ce
WORLD NEUROSURGERY
Q1
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News items of interest may be forwarded to: Felipe C. Albuquerque, M.D. Section Editor, WORLD NEUROSURGERY News E-mail: [email protected]
that inhibition of Shh results in decreased tumor growth and increased survival, likely due to its interaction with PlGF but also possibly due to cross-talk with other pathways.
Issam Awad, M.D.
Section Editor, WORLD NEUROSURGERY News
Section Editor, WORLD NEUROSURGERY News
For the first time, Snuderl et al. demonstrate the intricacies of the PlGF/Nrp1 axis in relation to medulloblastoma and its positive effects on tumor spread and growth. Knowing these 2 molecules
print & web 4C=FPO
95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140
Felipe C. Albuquerque, M.D.
Figure 1. (continued) (B) Blood GLuc measurement is a marker of total tumor burden. aPlGF [R] (TB403) therapy is initiated 3 weeks (D283-MED) or 4 weeks (D341-MED) after implantation of medulloblastoma tumors. Treated tumors showed a significant decrease in total tumor burden (*P < 0.001 at endpoint, n ¼ 10/group, mean SEM). Error bars represent SEM. (C) Survival was significantly increased in both orthotopic models with anti-PlGF inhibition (**P < 0.0001, n ¼ 10/ group). The D283 model was treated with both the Roche antibody TB403 (aPlGF [R]) and the Genentech antibody C9.V2 (aPlGF [G]). The D341 model was treated with TB-403. All aPlGF [R]-treated mice that survived at the end of study showed no clinical symptoms. (D, E) Murine-specific anti-PlGF Ab 5D11D4 (amPlGF) shows similar effect in Smo/Smo spontaneous model of medulloblastoma. (D) At the endpoint of the study, amPlGF-treated animals showed no clinical symptoms, such as hunched posture, and had preserved body weight (**P ¼ 0.0044, n ¼ 8/group) and (E) significant decreased tumor size (measured in cross-section, **P ¼ 0.047 and P ¼ 0.01, amPlGF and aPlGF as compared to corresponding controls, respectively; n ¼ 8/group, 2 separate experiments, animals randomized by age and sex). Mice were treated with the murine-specific antibody 5D11D4 (amPlGF) or the Genentech anti-PlGF antibody (aPlGF [G]). Error bars represent SEM. (From: Snuderl M, Batista A, Kirkpatrick ND, et al: Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065-1076, 2013.)
WORLD NEUROSURGERY - (-): 2-4, - 2013
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World Neurosurgery News
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collectively act to sustain tumor survival, new therapies may be directed at inhibition of these factors or some downstream product. Although inhibition of PlGF and Nrp1 resulted in
REFERENCE 1. Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar 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,
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substantial tumor regression and improved survival, it never led to complete tumor obliteration, indicating the presence of a yet unknown resistance mechanism.
Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK: Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065-1076, 2013.
Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona, USA 1878-8750/$ - see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2013.05.006
- (-): 2-4, - 2013
FLA 5.1.0 DTD WNEU1935_proof 23 May 2013 4:20 pm ce
WORLD NEUROSURGERY
245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302
Wyatt Ramey and M.Yashar S. Kalani
Medulloblastoma remains the most common malignant pediatric brain tumor. Despite high survival rates associated with treatment, conventional regimens possess several serious morbidities. Consequently, the need for safer treatment alternatives with fewer longterm sequelae has prompted investigation into inhibition of specific factors 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 in concert to foster medulloblastoma growth and spread, as potential targets of antitumor therapy (1). Because PlGF expression was not
limited to any particular genetic subtype of medulloblastoma, inhibition of PlGF (Figure 1) can be used as an alternative to standard regimens. PlGF acts by stimulating vital growth factors via the mitogen-activated protein kinase (MAPK) cascade, an action mediated by its receptor Nrp1. Nrp1 is essential to PlGF function and represents a poor prognosticator when overexpressed in medulloblastoma. Sonic hedgehog (Shh) secreted by tumor cells acts via paracrine signaling to trigger stromal release of PlGF, a concept previously unknown in this cancer’s pathophysiology that potentials a novel site for therapeutic development. It is therefore not surprising
print & web 4C=FPO
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47
Figure 1. Inhibition of placental growth factor (PlGF) leads to regression of medulloblastoma. (A) Whole-body imaging of D283-MED tumors transfected with GLuc. We initiated treatment 3 weeks after implantation, when tumors produced clinical symptoms and were apparent by whole-body imaging (arrowheads). Additionally, small spinal cord drop metastases were observed at 3 weeks (arrows). At 6 weeks, IgG-treated control tumors have progressed both in the cerebellum (red arrowheads) and spine (red arrows), whereas aPlGF [R] (TB403)-treated tumors have regressed in both the cerebellum (yellow arrowheads) and spine (yellow arrows). (continues)
2
www.SCIENCEDIRECT.com
- (-): 2-4, - 2013
FLA 5.1.0 DTD WNEU1935_proof 23 May 2013 4:20 pm ce
WORLD NEUROSURGERY
Q1
48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94
News items of interest may be forwarded to: Felipe C. Albuquerque, M.D. Section Editor, WORLD NEUROSURGERY News E-mail: [email protected]
that inhibition of Shh results in decreased tumor growth and increased survival, likely due to its interaction with PlGF but also possibly due to cross-talk with other pathways.
Issam Awad, M.D.
Section Editor, WORLD NEUROSURGERY News
Section Editor, WORLD NEUROSURGERY News
For the first time, Snuderl et al. demonstrate the intricacies of the PlGF/Nrp1 axis in relation to medulloblastoma and its positive effects on tumor spread and growth. Knowing these 2 molecules
print & web 4C=FPO
95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140
Felipe C. Albuquerque, M.D.
Figure 1. (continued) (B) Blood GLuc measurement is a marker of total tumor burden. aPlGF [R] (TB403) therapy is initiated 3 weeks (D283-MED) or 4 weeks (D341-MED) after implantation of medulloblastoma tumors. Treated tumors showed a significant decrease in total tumor burden (*P < 0.001 at endpoint, n ¼ 10/group, mean SEM). Error bars represent SEM. (C) Survival was significantly increased in both orthotopic models with anti-PlGF inhibition (**P < 0.0001, n ¼ 10/ group). The D283 model was treated with both the Roche antibody TB403 (aPlGF [R]) and the Genentech antibody C9.V2 (aPlGF [G]). The D341 model was treated with TB-403. All aPlGF [R]-treated mice that survived at the end of study showed no clinical symptoms. (D, E) Murine-specific anti-PlGF Ab 5D11D4 (amPlGF) shows similar effect in Smo/Smo spontaneous model of medulloblastoma. (D) At the endpoint of the study, amPlGF-treated animals showed no clinical symptoms, such as hunched posture, and had preserved body weight (**P ¼ 0.0044, n ¼ 8/group) and (E) significant decreased tumor size (measured in cross-section, **P ¼ 0.047 and P ¼ 0.01, amPlGF and aPlGF as compared to corresponding controls, respectively; n ¼ 8/group, 2 separate experiments, animals randomized by age and sex). Mice were treated with the murine-specific antibody 5D11D4 (amPlGF) or the Genentech anti-PlGF antibody (aPlGF [G]). Error bars represent SEM. (From: Snuderl M, Batista A, Kirkpatrick ND, et al: Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065-1076, 2013.)
WORLD NEUROSURGERY - (-): 2-4, - 2013
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FLA 5.1.0 DTD WNEU1935_proof 23 May 2013 4:20 pm ce
Q2
3
141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186
World Neurosurgery News
187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244
collectively act to sustain tumor survival, new therapies may be directed at inhibition of these factors or some downstream product. Although inhibition of PlGF and Nrp1 resulted in
REFERENCE 1. Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar 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,
4
www.SCIENCEDIRECT.com
substantial tumor regression and improved survival, it never led to complete tumor obliteration, indicating the presence of a yet unknown resistance mechanism.
Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK: Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065-1076, 2013.
Division of Neurological Surgery, Barrow Neurological Institute, Phoenix, Arizona, USA 1878-8750/$ - see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.wneu.2013.05.006
- (-): 2-4, - 2013
FLA 5.1.0 DTD WNEU1935_proof 23 May 2013 4:20 pm ce
WORLD NEUROSURGERY
245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302