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. 2015 Oct 19;6(42):44254–44273. doi: 10.18632/oncotarget.5471

Figure 4. Experimental brain metastasis models to validate the therapeutic effect of a thalidomide derivative.

Figure 4

Figure 4

Lenalidomide, 50 mg/Kg/day, alone or in combination with Docetaxel 15 mg/Kg/day and NVP-AUY922 (NVP) 30 mg/Kg/day. Docetaxel was administered every 4 days for 2 weeks and NVP-AUY922 every 2 days for 2 weeks. A. Representative images show bioluminescence in animals at day 5, 12 and 22 from the start of LND treatment 50 mg/Kg/day every day (Celgene Corporation, Summit, NJ). B. The survival time (box plot) of mice treated with LND (N = 8) or with vehicle (Control, N = 8) was evaluated using the log-rank test (p = 0.0802) and the differences observed in the survival rate between the two groups (treated or not with LND) are represented. C. IHC analysis in paraffin-embedded experimental brain metastasis (x 20) shows the downregulation of FN14 in mice treated with LND. D. IHC analysis in paraffin-embedded experimental brain metastasis (x 20). Representative figures showing the upfront of the metastasis invading the brain tissue in controls (upper part of the figure). Each protein expressed is indicated. CD31 a. GFAP b. and TWEAK c. Decreased angiogenesis d. few reactive astrocytes e. and downregulation of TWEAK f. indicated with arrows in tissues from mice treated with LND with regard to controls (lower part of the figure). E. Representative images show bioluminescence in animals at day 22 from the start of indicated treatments. The bioluminescence data were transformed using the log(1+x) function (where x = AvR), in order to obtain a more regular and positive distribution. Subsequently, these data were normalized by subtracting the first observation (day 14) from each of the following observations. F. The survival time (box plot) of mice treated with NVP-AUY922 (N = 6) alone or in combination with LND (N = 6) are shown. The differences in mouse survival were statistically significant in NVP-AUY922 + LND vs. CTR (p = 0.012) and NVP-AUY922 alone vs NVP-AUY922 + LND (p = 0.033); but the survival of mice treated only with NVP-AUY922 and controls was similar (p = 0.351). G. IHC of brain metastasis from mice treated with NVP-AUY922 alone and in convination with LND. The expression of GFAP indicative of reactive astrocytes is higher in NVP-AUY922 + LDN group than in brain metastasis from mice treated with NVP-AUY922 alone. H. Athymic Nude-Foxn1nu female mice. The xenograft expression of GRP94 and FN14 is shown in the upper part, in tumoral cells (GRP94) and in tumor and estromal cells (FN14). The statistical differences between groups of treatment (*): control treated with vehicle (N=17), Docetaxel (N=10), LND (N=16), NVP (N=15), NVP+LND (N=9) and Docetaxel+LND (N=20) according the volume slope are indicated at the bottom of the figure.