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. Author manuscript; available in PMC: 2017 May 31.
Published in final edited form as: Science. 2016 May 20;352(6288):aad3018. doi: 10.1126/science.aad3018

Figure 7. Combination of CSF-1R inhibition and IGF-1R inhibition significantly improves outcome in preclinical models.

Figure 7

(A) Long-term trial design for testing BLZ945 and OSI906 combination therapy on PDG tumors. High-grade tumors were treated with BLZ945 until recurrent tumors developed (trial design 1) or until dormancy (28d, trial design 2), whereupon OSI906 was either added (with continuous BLZ945) or switched (discontinued BLZ945). (B) Survival of animals with recurrent tumors treated either with BLZ945 alone (n=33), OSI906 alone (n=13), or BLZ945 in combination with OSI906 (n=13; trial design 1 in Fig. 7A). Combination therapy of BLZ945+OSI906 led to an increase in overall survival (Log-rank Mantel-Cox test, P<0.001), and in median survival following recurrence (63d) compared to BLZ945 (13d), or OSI906 (12d) monotherapy. (C) Ki67:CC3 (cleaved caspase 3) proliferation:apoptosis index from immunofluorescent staining of recurrent tumors treated with BLZ945 alone versus BLZ945+OSI906 for 2 weeks (Mann-Whitney test, P<0.01, n=7–8 mice). (D) Representative H&E and immunofluorescent images corresponding to data in (C). Scale bars = 50 μm. (E) Bioluminescent imaging (BLI) from orthotopically xenografted patient-derived tumorspheres (TS573) that were subject to 24d of treatment with BLZ945 (red) versus vehicle control (grey). Results demonstrate that treatment with BLZ945+OSI906 blunts outgrowth of rebound tumors compared to BLZ945+vehicle. Mann-Whitney test was used to calculate P-values for each time point (n=5–20 mice). (F) Ki67:CC3 index from immunofluorescent staining of TS573 orthotopic xenograft tissues (Mann-Whitney test, P<0.01, n=5 mice per group). (G) Kaplan-Meier analysis of PDG animals treated either with BLZ945 alone (n=90; same cohort as presented in Fig. 1D), OSI906 alone (n=6) or with BLZ945 in combination with OSI906 during dormancy (n=9; trial design 2 in Fig. 7A). Combination therapy of BLZ945+OSI906 extended overall survival compared to either monotherapy. Log-rank Mantel-Cox test was used to calculate significance. (H) BLI of orthotopically xenografted U251 cells genetically engineered to express an IGF1R-targeted doxycycline (dox)-inducible shRNA (sh; n=15–16 mice; purple lines) or a scrambled control vector (Scr; n=4–5 mice; grey lines). Colored arrows indicate respective administration of dox. Graph shows two combined shRNAs; data for individual hairpins are shown in fig. S13E. Mann-Whitney test was used to calculate significance.