Figure 6.
In vivo anti-MM activity of MIR17PTi. (A) In vivo growth inhibition of NCI-H929, AMO1luc+, or ABZBluc+ subcutaneous xenografts by MIR17PTi (2 mg/kg). Treatments were performed on days 1, 4, 8, 15, and 22 (NCI-H929) or 1, 4, 8, and 11 (AMO1luc+ and ABZBluc+). Mice were also treated with bortezomib (BZB) as positive control (1 mg/kg on days 1, 4, 8, and 11). Numbers of xenografted mice: NCI-H929, n = 17 (no treatment [NT], n = 7; MIR17PTi, n =10); AMO1luc+, n = 13 (NT, n = 5; MIR17PTi, n = 5; BZB, n = 3); ABZBluc+, n = 12 (NT, n = 4; MIR17PTi, n = 5; BZB, n = 3). Treatments were performed systemically (IV). Tumor volumes at day 33 (NCI-H929) or day 12 (AMO1luc+ and ABZBluc+) after the first treatment are reported. Supporting images and BLI measurements are shown in supplemental Figure 14. (B) Survival curves (Kaplan-Meier) relative to mice reported in panel A (log-rank test P < .05). Survival was evaluated from the first day of treatment until death or euthanasia. Percentage of mice alive is shown. (C) qRT-PCR analysis of pri-mir-17-92 in retrieved NCI-H929 (n = 3) or AMO1luc+ (n = 1) subcutaneous xenografts 2 days after the last dose of the treatment period with MIR17PTi (on days 1, 4, 8, and 11), as compared with tumor retrieved from untreated animals (NCI-H929, n = 1; AMOluc+, n = 1). Animals used for this analysis were not considered for tumor growth and survival evaluations. The results shown are average pri-mir-17-92 expression levels after normalization with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and ΔΔCt calculations. (D) qRT-PCR analysis (left) and western blotting (right) of BIM in retrieved tumors (AMO1) from MIR17PTi-treated (n = 1) or -untreated (n = 1) mice. The qRT-PCR results shown are average BIM expression levels after normalization with GAPDH and ΔΔCt calculations. GAPDH was used as protein loading control. (E) Schematic representation of SCID-hu model (left) and INA-6 growth within human fetal bone chips subcutaneously implanted in NOD SCID mice (right). Plasmatic levels of soluble interleukin-6 receptor (IL-6R) were used to evaluate tumor growth. Systemic treatments with MIR17PTi (2 mg/kg; days 1, 4, 8, 15, and 22) started at day 22. Effects of MIR17PTi were evaluated at the end of treatment (day 44). A total of 8 mice were treated as follows: NT (n = 4), MIR17PTi (n = 4). *P < .05. BMM, BM microenvironment.

In vivo anti-MM activity of MIR17PTi. (A) In vivo growth inhibition of NCI-H929, AMO1luc+, or ABZBluc+ subcutaneous xenografts by MIR17PTi (2 mg/kg). Treatments were performed on days 1, 4, 8, 15, and 22 (NCI-H929) or 1, 4, 8, and 11 (AMO1luc+ and ABZBluc+). Mice were also treated with bortezomib (BZB) as positive control (1 mg/kg on days 1, 4, 8, and 11). Numbers of xenografted mice: NCI-H929, n = 17 (no treatment [NT], n = 7; MIR17PTi, n =10); AMO1luc+, n = 13 (NT, n = 5; MIR17PTi, n = 5; BZB, n = 3); ABZBluc+, n = 12 (NT, n = 4; MIR17PTi, n = 5; BZB, n = 3). Treatments were performed systemically (IV). Tumor volumes at day 33 (NCI-H929) or day 12 (AMO1luc+ and ABZBluc+) after the first treatment are reported. Supporting images and BLI measurements are shown in supplemental Figure 14. (B) Survival curves (Kaplan-Meier) relative to mice reported in panel A (log-rank test P < .05). Survival was evaluated from the first day of treatment until death or euthanasia. Percentage of mice alive is shown. (C) qRT-PCR analysis of pri-mir-17-92 in retrieved NCI-H929 (n = 3) or AMO1luc+ (n = 1) subcutaneous xenografts 2 days after the last dose of the treatment period with MIR17PTi (on days 1, 4, 8, and 11), as compared with tumor retrieved from untreated animals (NCI-H929, n = 1; AMOluc+, n = 1). Animals used for this analysis were not considered for tumor growth and survival evaluations. The results shown are average pri-mir-17-92 expression levels after normalization with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and ΔΔCt calculations. (D) qRT-PCR analysis (left) and western blotting (right) of BIM in retrieved tumors (AMO1) from MIR17PTi-treated (n = 1) or -untreated (n = 1) mice. The qRT-PCR results shown are average BIM expression levels after normalization with GAPDH and ΔΔCt calculations. GAPDH was used as protein loading control. (E) Schematic representation of SCID-hu model (left) and INA-6 growth within human fetal bone chips subcutaneously implanted in NOD SCID mice (right). Plasmatic levels of soluble interleukin-6 receptor (IL-6R) were used to evaluate tumor growth. Systemic treatments with MIR17PTi (2 mg/kg; days 1, 4, 8, 15, and 22) started at day 22. Effects of MIR17PTi were evaluated at the end of treatment (day 44). A total of 8 mice were treated as follows: NT (n = 4), MIR17PTi (n = 4). *P < .05. BMM, BM microenvironment.

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