Article Figures & Data
Figures
- Figure 1.
MLN8237 combined with docetaxel results in antitumor activity in three models of triple-negative breast cancer, including the cell line xenograft MDA-MB-231 (A), the primary human breast tumor xenograft PHTX-02B (B), and the primary human breast tumor xenograft PHTX-14B (C). Mice were treated for 21 days with MLN8237 (p.o., every day), docetaxel (i.v., every week × 3), or the combination of both at the indicated doses. Tumors were measured twice weekly with vernier calipers; error bars, SEM. The dotted line box indicates the 21-day treatment period.
- Figure 2.
MLN8237 and docetaxel exposures are similar when dosed alone or in combination and result in an increased mitotic index. A single dose of MLN8237 (10 mg/kg), docetaxel (5 mg/kg), or the combination of both, was administered to mice bearing MDA-MB-231 xenografts. Blood and tumor samples were taken at multiple times out to 24 hours. A, MLN8237 and docetaxel concentrations are shown in both the plasma and the MDA-MB-231 tumor xenograft. B, MDA-MB-231 tumor sections (n = 3/group) were stained with fluorescently labeled antibodies directed against phosphorylated Histone H3 on serine 10 (pHistH3) or MPM2 and the staining was quantified as described in the Materials and Methods. Error bars, SD.
- Figure 3.
H&E staining of tumor xenografts results in morphologic changes following single agent or combination treatment with MLN8237 and docetaxel. Mice bearing PHTX-14B (A and B) and MDA-MB-231 (C and D) xenografts were treated with vehicle, MLN8237 (10 mg/kg p.o., every day), docetaxel (5 mg/kg i.v. every 7 days), or the combination of both for 10 days. On day 10, tissues were harvested and fixed in 10% neutral buffered formalin. Tumor sections were stained by H&E and imaged. Tumor and nontumor areas were quantified in regions of the tumors that maintained viable cells using Definiens Tissue Studio software.
- Figure 4.
MLN8237 administered on an intermittent 3 days on/4 days off schedule combined with docetaxel results in significant antitumor activity in two primary breast tumor models, PHTX-02B (A) and PHTX-14B (B). Tumor-bearing mice were treated with MLN8237 administered once daily for 3 days for 3 weeks (3on/4off), docetaxel administered once weekly for 3 weeks, or the combination of both. Tumors were measured twice weekly with vernier calipers; error bars, SEM. The dotted line box indicates the 21-day treatment period.
- Figure 5.
MLN8237 combined with paclitaxel results in significant antitumor activity in the MDA-MB-231 (A) and PHTX-14B (B) tumor models. Tumor-bearing mice were treated for 21 days with MLN8237 (p.o., every day), paclitaxel (i.v., every 7 days), or the combination of both. Tumors were measured twice weekly with vernier calipers; error bars, SEM. The dotted line box indicates the 21-day treatment period.
- Figure 6.
A surface response plot relating MLN8237 and paclitaxel exposures to TGI (% TGI) generated from multiple in vivo efficacy studies in mice bearing the MDA-MB-231 xenograft (blue dots; A). An isobologram derived from the surface response plot (B). Clinically achieved exposures of MLN8237 (10 or 40 mg twice a day) and paclitaxel (60 or 80 mg/m2) from the NCT01091428 study represented by the red stars were mapped onto the isobologram by correcting for mouse-to-human variation in plasma protein binding and maximum tolerated exposures for both agents [AUCu/CF (correction factor)]. Predicted TGI derived from the exposure–efficacy surface response plot with increasing doses of MLN8237 administered twice a day with or without paclitaxel (C).
Tables
- Table 1.
Antitumor activity summary of MLN8237 combined with docetaxel
Model MLN8237 dose (every day or 3 on/4 off) Docetaxel dose (every 7 days × 3) TGIc (%) TGD (days)d Outcome (AUC)e MDA-MB-231a 3 mg/kg 5 mg/kg 54.2 7 Synergistic 10 mg/kg 5 mg/kg 91.8 >48 Synergistic 10 mg/kg 5 mg/kg 67.3 11 Synergistic 3 mg/kg 10 mg/kg 112.7 46 Synergistic 10 mg/kg 10 mg/kg 117.9 >106 Synergistic 10 mg/kg 10 mg/kg 106.1 >41 Synergistic PHTX-02Bb 10 mg/kg 5 mg/kg 95.2 35 Synergistic 20 mg/kg 5 mg/kg 101.7 51 Synergistic 20 mg/kg 5 mg/kg 99.3 49 Additive 20 mg/kg 3 on/4 off 5 mg/kg 103.9 >51 Synergistic PHTX-14Bb 10 mg/kg 5 mg/kg 123.4 >45 Synergistic 20 mg/kg 5 mg/kg 125.4 >45 Synergistic 10 mg/kg 10 mg/kg 128 >45 Synergistic 20 mg/kg 10 mg/kg 134 >45 Synergistic 3 mg/kg 3 on/4 off 5 mg/kg 85.6 38 Additive 20 mg/kg 3 on/4 off 5 mg/kg 123 >60 Synergistic 3 mg/kg 3 on/4 off 10 mg/kg 121.5 >60 Additive 20 mg/kg 3 on/4 off 10 mg/kg 140.1 >76 Synergistic -
↵aOrthotopic MDA-MB-231 xenografts were grown in the fat pad of nude mice and treated with MLN8237 administered orally for 21 days with docetaxel dosed i.v. once per week.
-
↵bPrimary breast cancer models were grown subcutaneously in SCID (PHTX-14B) or NOD (PHTX-02B) mice and treated with MLN8237 administered orally for 21 days with docetaxel dosed i.v. once per week.
-
↵cTGI = (Δ treated/Δ control) × 100/Δ control, was calculated on the last day of treatment.
-
↵dTGD, the difference in days between the control and the treated groups to reach 1,000 mm3. > denotes that the treatment group was terminated before reaching 1,000 mm3.
-
↵eSynergy analysis based on the AUC values days 0 to 20.
-
- Table 2.
Antitumor activity summary of MLN8237 combined with paclitaxel
Model MLN8237 dose (every day) Paclitaxel dose (every 7 days × 3) TGIc (%) TGD (days)d Outcome (AUC)e MDA-MB-231a 20 mg/kg 30 mg/kg 101.4 35 Synergistic 20 mg/kg 20 mg/kg 94.3 26 Synergistic 20 mg/kg 20 mg/kg 96.3 24 Synergistic 20 mg/kg 15 mg/kg 85.7 16 Additive 20 mg/kg 10 mg/kg 45.87 4 Additive 20 mg/kg 5 mg/kg 43.6 4 Additive 10 mg/kg 30 mg/kg 102.4 31 Synergistic 10 mg/kg 20 mg/kg 81.9 13 Additive 10 mg/kg 15 mg/kg 85.6 14 Additive 10 mg/kg 10 mg/kg 42.3 4 Additive 3 mg/kg 20 mg/kg 69.2 10 Additive 3 mg/kg 20 mg/kg 60.5 7 Additive 3 mg/kg 10 mg/kg 21.7 2 Additive 3 mg/kg 5 mg/kg 20.8 2 Additive PHTX-14Bb 20 mg/kg 20 mg/kg 103 >14 Synergistic 20 mg/kg 10 mg/kg 84 >14 Synergistic 3 mg/kg 20 mg/kg 72 >14 No data -
↵aOrthotopic MDA-MB-231 xenografts were grown in the fat pad of nude mice and treated with MLN8237 administered orally for 21 days with paclitaxel dosed i.v. once per week.
-
↵bPrimary breast cancer models were grown in SCID mice and treated with MLN8237 administered orally for 21 days with paclitaxel dosed i.v. once per week.
-
↵cTGI = (Δ treated/Δ control) × 100/Δ control, was calculated on the last day of the treatment.
-
↵dTGD, the difference in days between the control and the treated groups to reach 1,000 mm3. > denotes that the treatment group was terminated before reaching 1,000 mm3.
-
↵eSynergy analysis based on the AUC values days 0 to 20.
-
Supplementary Figures 1-5
Files in this Data Supplement:
- Data Supplement - Supplementary Figure 1. Sample simulated time-course of paclitaxel and MLN8237 PK after and the pharmacokinetic parameters used for MLN8237 and paclitaxel required to generate the exposure - efficacy model. Supplementary Figure 2. Predicted versus observed % TGI resulting from the best fit of the dose response surface to the xenograft tumor growth data. Supplementary Figure 3. Cleaved caspase 3 staining of tumor xenografts following single agent or combination treatment with MLN8237 and docetaxel in the PHTX-14B and MDA-MB-231 xenografts. Supplementary Figure 4. MLN8237 administered on an intermittent 3 days on / 4 days off schedule combined with paclitaxel results in additive antitumor activity in the MDA-MB-231 model. Supplementary Figure 5. MLN8237 and paclitaxel exposures are similar when dosed alone or in combination.
- Data Supplement - Supplementary Figure Legends describing Supplementary Figures 1-5.
Volume 13, Issue 9
