悪性脳腫瘍に対する血管新生抑制療法

Tumor
Glomeruloid
Vascular
Proliferation

VEGF
HIF1αnecrosis③③
Co-option ofExisting vessels
By tumor cells

Tumor
Vessel②①Endothelialcell④ EPC

Basement
membrane
Pericyte

栄養源である血管を止めれば腫瘍は育たない
1Suramin inhibits glioma angiogenesis
Migration

Tube formation

Proliferation (C6 model)

Control

Suramin

CAM assay

U-PA production

U-PA
bFGF+ + + +Suramin (ug/ml) 0 0 100 250 500

Control

SuraminTumor Volume (mm3)Interferon-β inhibits glioma growth
Control
INF-Low
INF-High

20000
18000
16000

NO INF-ß

14000

CONT

12000
10000
8000

LOW6000400010mm

HIGH

2000

051015202530354045

マウス皮下悪性脳腫瘍モデル

Days After Tumor Implantation
VEGF
Ag

Control

INF-ß
Low

INF-ß
High
Western analysis

VEGF

Down-regulation of VEGF
Up-regulation of IP10

IP10IP10Ag

3

TSP-1 Transfectant Tumor Growth
RT-PCR
Neo

5000

P
TSP1

ß-actin

Tumor Volume (mm3)

TSP

Parent U87 cells

PTSP
NEO

4000

Neo-transfectant

3000
2000

TSP1-transfectant

1000

CM
Western00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Days After Implantation

TSP1TSPTSP1VEGF

NeoP

Positive control

U251 CMVEGFTSP1とVEGFのリンク

U87 VEGF
AgCM

GBM

AAGBM

AA

Survival rate

膠芽腫とVEGF

1.8.6

Brain

<1000pg/mg (n 17)

.4.20

GBM

p=0.0002>1000pg/mg (n 24)
0 10 20 30 40 50 60 70 80 90
Time (mo)Cancer Res 1996, BTPA 2005

ベバシズマブの膠芽腫への効果（U87 マウスモデル）
Tumor Volume (mm3)“増殖の抑制と生存期間の延長”“腫瘍血管新生の抑制”

Control
ACNU
VEGF AbACNU+VEGF Ab

5000

40003000

Control

皮下20001000
0102030
Days After Tumor Implantation040

皮下CD31

Survival Rate

1.00.8Control
ACNU

0.6

VEGF AbACNU+VEGF Ab

VEGFAntibody0.4

脳内0.2

CD31

00

10 20 30 40 50 60
Days after Tumor Implantation70

Neuro-Oncol 2003

Body Weight (g)Tumor Volume (mm3)Metronomic CPT11 schedule is effective and not-toxic
Conventional Treatment

Metronomic Treatment

CPT11 day11-15, day 18-22

CPT11 everyday day 1-21

4000
3500
3000
2500
2000
1500
1000
500
03000

Control
10 mg/kg x10 = 100mg/kg
40 mg/kg x10 = 400mg/kg

Control
1mg/kg x21 = 21mg/kg
4mg/kg x21 = 84mg/kg

2500

2000
1500
1000
500

030
2826242220181614
121051015202530

510152025

Days after implantation

13028
26
24
222018161412
10

Body weight loss (+)
0030

357

911 13 15 17 19

Body weight loss (-)
0510152025

Days after implantation

J Neurooncol 2010

Metronomic CPT11 schedule inhibits hypoxia
Low

Control

Hypoxic area (pymonidazole)

HighControl
HIF-1αVEGF165

VEGF

VEGF121β actinVEGF121/ actin ratio

VEGF165/ actin ratio
32.5

32.5
2
1
0

control

lowdosehighdose0

CPT11p<0.01

654
32

10.5

0.5

9HIF-1α / actin ratio

8721.51.510

10control

lowdosehighdosecontrol**

lowdosehighdose

J Neurooncol 2010

脳腫瘍に対する血管新生抑制療法取り組んでいること• 血管新生抑制の抵抗性の克服– Vessel co-optionの分子メカニズムと抑制– Vessel mimicryの分子メカニズムと抑制– 低酸素誘導因子の抑制による低酸素の解除• 免疫療法との併用効果
9Resistance to anti–VEGF / VEGFR strategies
in glioblastoma (GBM)

Co-option Intussusception Mimicry

Pericyte

Hypoxia

Christine Lu-Emerson et al. JCO
2015;33:1197-1213

Mechanisms of vessel formation
VEGF dependent

Sprouting

Vasculogenesis

Intussusception

Co-option
Infiltrative growth

VascularmimicryEndotheldifferentiation
Carmeliet Nature 2011

Vessel co-option

VEGF independentStandard Tx

Anti-angiogenic Tx

腫瘍辺縁部でco-optionが増えている
Di-Tomaso Cancer Res 2011

Vasculogenic mimicry in GBM
VEGF independent

CD34 (-)“PECAM”

Type IV
Collagen (+)

Yao Protein Cell 2011
Hallani et al. Brain 2010

Dunleavey, J Nat Commun 2014