Cartilage Dysplasia and Tissue Mineralization in the Rat Following Administration of a FGF Receptor Tyrosine Kinase Inhibitor

Abstract

PD176067 is a reversible and selective inhibitor of fibroblast growth factor receptor tyrosine kinase, and was in preclinical development as an angiogenesis inhibitor for the treatment of solid tumors. A 14-day oral toxicity study of PD176067 in young female rats (7 weeks old) was conducted at doses of 2.5, 5, and 10 mg/kg/day (15, 30, and 60 mg/m 2 , respectively). Skeletal changes, and vascular and soft tissue mineralization were observed as primary drug-related toxicities. To determine if these changes are specific to young, rapidly growing animals with increased vascular and osseous development, PD176067 was administered to mature (11 months old) rats. Female rats received PD176067 by gavage for 14 days at doses of 2.5, 5, and 10 mg/kg/day and necropsied on day 15. Clinical signs of toxicity were seen at ≥5 mg/kg and one death occurred at 10 mg/kg. Physeal dysplasia (distal femur, proximal tibia, sternum) occurred in all drug-treated animals and was characterized by dose-related increased thickness of the zones of chondrocyte proliferation and hypertrophy, and marked thickening of the zone of ossification. Cartilage hyperplasia was characterized by proliferation of chondrocytes along margins of the synchondrosis and subperiosteum of sternebrae. Serum phosphorus levels increased 47% and 166% at 5 and 10 mg/kg, respectively. Mineralization of cardiac myocytes, aorta, various arteries, renal tubules, and gastric mucosa and muscularis was seen at 10 mg/kg, and consistent with the presence of calcium-phosphorus deposition. Physeal changes occurred at similar plasma PD176067 exposures in young and mature rats (AUC ≥ 4.83 µg · hr/mL). PD176067 produced morphologically similar lesions in young and adult rats.

Inhibition of ALK5 Signaling Induces Physeal Dysplasia in Rats

“…In TGF-β and FGF null mice with physeal dysplasia, there is increased expression and synthesis of IHH within several zones of the physis, which may also mediate some of the morphologic changes (Serra et al, 1997;Liu et al, 2002). bFGF inhibits chondrocyte proliferation by inhibiting IHH, therefore inhibition of bFGF signaling is likely to induce chondrocyte proliferation, as was suggested in our studies and those with an FGF receptor inhibitor (Baron et al, 1994;Brown et al, 2005). Chondrocyte differentiation is also modulated by bFGF, and both actions appear to antagonize effects of the MMPs (Baron et al, 1994;Van der Eerden et al, 2003).…”

“…The FGF receptor kinase inhibitor used (PD176067) also had some VEGF receptor kinase inhibitory activity. Vascularization and endothelial cell proliferation, which are known to be major factors controlling matrix mineralization at the ossification zone of the metaphysis, are greatly enhanced by either bFGF or VEGF treatment (Cross and Claesson-Welsh, 2001;Brown et al, 2005).…”

“…In a recent study, administration of an FGF receptor kinase inhibitor to rats also resulted in cartilage dysplasia, physeal dysplasia, and chrondrocyte proliferation, but with marked thickening of the zone of ossification and generalized soft tissue mineralization (which were not features in the ALK5 inhibitor cases) (Brown et al, 2005). The FGF receptor kinase inhibitor used (PD176067) also had some VEGF receptor kinase inhibitory activity.…”

Blocking the FGF/FGFR system as a ⿿two-compartment⿿ antiangiogenic/antitumor approach in cancer therapy

“…Relevant to this latter point, blockade of FGFR signalling by selective or broad-spectrum TK inhibitors has been associated with toxicity [146] and a monoclonal antibody directed against FGFR1 has failed because of severe weight loss associated with hypothalamic binding [156]. Interestingly, at variance with the hyperphosphatemic effect of FGFR TK inhibitors in preclinical models [157] and cancer patients [146], long-term administration of the small molecule FGF trap NSC12 does not affect the blood levels of phosphorus, calcium and FGF23 in tumor-bearing mice [120]. These observations are in keeping with the safety profile in murine tumor models of the FGFR1-derived FGF trap FP-1039 [124] and of the allosteric multi-FGFR blocker SSR128129E [148].…”

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

“…Determination of the functional and in vivo requirement of FGF signaling in the vasculature may provide insight into opportunities for targeted cell-specific therapeutic interventions, given the systemic toxicity associated with global FGFR inhibition (36)(37)(38)(39) and potential risks associated with global FGFR activation. Because the EC is often a therapeutic target, it is essential to know whether EC FGF signaling is directly required during development, tissue homeostasis, and response to injury.…”