The RTK inhibitor ABT-869, alone and in combination with paclitaxel and/or zoledronic acid, demonstrates significant reduction in the development of both osteoblastic (LuCap 23.1) and osteolytic (PC3-M-Luciferase) tumors intratibially

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ABT-869 (ABT), a receptor tyrosine kinase inhibitor (RTKI) currently in Phase 1 clinical trials, is a potent inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factors (PDGF-α and -β). It also exhibits potent inhibition of mutant kinases, such as fms-like tyrosine kinase 3 (FLT3), c-kit (CD117) and colony stimulating factor-1 receptor (CSF1R). Prostate carcinoma (PC) is known to be hypervascularized/angiogenic and overexpression of VEGF and PDGF has been previously reported. Such attributes indicate antiangiogenic therapy as an attractive therapeutic strategy for PC. As bone metastases are responsible for most of the morbidity associated with this disease, we assessed the therapeutic effect of the antiangiogenic agent ABT, alone or in combination with cytotoxic therapies, in LuCap 23.1 and PC-3M-luc-C6 tumors implanted intratibially.
 LuCap 23.1, derived from a lymph node metastasis of human PC, produces high PSA levels that correlate with tumor burden and forms osteoblastic lesions when injected intratibially into the proximal epiphysis of the right hind tibia in male SCID mice. At 8 weeks, animals were segregated into treatment groups based on serum PSA levels (19.13 ± 0.85 ng/ml). Mice were treated with vehicle, ABT [25 mg/kg/day (mkd), po, bid, 9 wks], paclitaxel (PTX; 25 mkd, ip, q4dX3) or ABT+PTX (25/25 mkd) and tumor growth was evaluated both by PSA levels and calculation of the area of increased calcification (AIC) due to osteoblastic growth, as analyzed by X-ray image analysis. At 17 weeks, percent tumor growth inhibition (%TGI), as monitored by PSA/AIC, respectively, was significantly different from vehicle for ABT, 97%/56%; PTX, 95%/54%; and ABT+PTX at >99%/56% (6/13 no PSA). The double combination was significantly lower than all other groups tested.
 In a second cohort of mice, bioluminescent PC-3M-luc-C6 osteolytic human PC cells, constitutively expressing luciferase, were injected intratibially in male SCID mice. On day 20, animals were randomized into treatment groups based on bioluminescent imaging (BLI) and received vehicle, ABT (25 mkd, po, bid, 3 wks), PTX (12.5 mkd, ip, q4dX3) or zoledronic acid (ZA; 0.25 mkd, sc, 2X/wk for 3 wks) alone or in combination. Progressive tumor development and inhibition/regression following drug treatment were observed and quantified in vivo using BLI. There was no effect on tumor burden by PTX or ZA alone, however, we did observe significant %TGI with PTX+ZA (55%), ABT (78%), ABT+PTX (91%), ABT+ZA (80%), and ABT+PTX+ZA (97%). Further, ABT+PTX+ZA was significantly more efficacious than any of the other treatments or combinations tested.
 Immunohistochemical and protein array analyses for phosphorylated RTK expression are being evaluated to delineate the potential underlying mechanisms of ABT antitumor efficacy in these models. Taken together, these data indicate significant single agent antitumor activity of ABT alone and improved efficacy in both osteolytic and osteoblastic models of PC when combined with PTX and/or ZA.