Abstract A233: Cabozantinib (XL184), a dual MET-VEGFR2 inhibitor, blocks osteoblastic and osteolytic progression of human prostate cancer xenografts in mouse bone.

Abstract

Background: Prostate cancer bone metastases are associated with high levels of MET expression, and both HGF, the only known ligand for MET, and VEGF appear to direct crosstalk between tumor cells, osteoblasts (OBs), and osteoclasts (OCs). Cabozantinib (cabo), a dual MET-VEGFR2 inhibitor, has shown clinical activity in patients with metastatic castration-resistant prostate cancer (CRPC), where a complete or partial resolution of lesions on bone scans, reduced pain, and soft tissue tumor regression were observed in the majority of patients studied. Therefore, the preclinical effects of cabo were studied in the human CRPC bone xenograft model ARCaPM, which expresses both MET and the VEGF co-receptor neuropilin-1. In addition, the effects of cabo on the differentiation and activity of human OCs and mouse OBs were studied in vitro. Methods: ARCaPM cells were injected bilaterally into the tibiae of nude mice on Day 1, and on Day 31 animals received either cabo at 10 or 30 mg/kg (mpk) or vehicle once-daily for 7 weeks (wks). Animals (n=10 for each dose group) were sacrificed at the end of the treatment period and X-ray images of the tibiae were taken. Five representative tibiae per group were also scanned and analyzed by a Scanco 40 micro-CT instrument. In addition, one tibia from each mouse was fixed, decalcified and embedded for histology and histomorphometry analyzes. The OC culture system consisted of CD34+ cells derived from human bone marrow that were cultured on bovine bone slices in the presence of growth factors including M-CSF and RANK-L. The OB culture system used mouse KS483 cells that differentiate into OBs capable of forming mineralized bone nodules. Results: X-ray and micro-CT imaging of tibiae harvested after the 7 wk treatment period indicated that cabo treatment blocked both the osteoblastic and osteolytic progression of ARCaPM xenograft tumors in bone, with concomitant increases in bone mineral density. Histomorphometry data indicated that tumors were present in 70% (7/10) of the tibiae in the control group but only 30% (3/10) and 20% (2/10) in the 10 mpk and 30 mpk cabo groups, respectively. Consistent with its anti-tumor effect in the bone, cabo treatment decreased the ratio of tumor to tissue area and increased the bone area relative to the tissue area in the analyzed tibia sections compared to vehicle. Histological analyzes indicated an increase in the number of OBs and no change in the number of OCs along the trabecular bone perimeter of tibiae from cabo-treated animals relative to vehicle controls. In the in vitro studies, cabo treatment resulted in reduced OC differentiation in a dose dependent manner but did not affect the ability of mature OCs to resorb bone. In contrast, in the OB studies cabo treatment resulted in a biphasic effect inducing OB differentiation and bone forming activity at the lower doses while reducing these parameters at higher doses. Conclusions: Cabo treatment resulted in diverse effects on the differentiation and function of OBs and OCs in vitro, and blocked both osteoblastic and osteolytic progression of ARCaPM xenograft tumors in bone. These data demonstrate a substantial impact of cabo on tumor cells, OBs, and OCs consistent with the observed clinical results in patients with CRPC. Studies to characterize the molecular mechanisms underlying these effects are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A233.

Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo

“…In addition, Schimmoller and colleagues have reported a dose-dependent decrease of osteoclast differentiation by CBZ in vitro that did not impede the ability of mature osteoclasts to resorb bone. They also found a biphasic effect of CBZ, with increased osteoblast differentiation and bone forming activity at the lower doses but a reduction at higher doses [38] . In vivo the tight coupling between osteoblasts and osteoclasts makes it difficult to separate the direct/indirect effects of therapeutic agents on these cells, in particular when both cell types express the target receptor(s).…”

Papillary renal cell carcinoma: A review of the current therapeutic landscape

“…Cabozantinib (XL184) is an oral, small molecule, multitargeted tyrosine kinase inhibitor with high activity against MET, VEGFR and RET [96]. Clinical trials conducted in metastatic prostate cancer have initially shown promising results on bone metastasis and pain control, although a recently completed phase III trial produced negative results [97].…”

Met in Urological Cancers

“…Cabozantinib (XL184) is an orally bioavailable TKI with potent activity against MET and VEGFR2. Cabozantinib blocked the progression of osteolytic and osteoblastic lesions in a xenograft model of CRPC in bone [ 36 ]. A phase II, randomized, discontinuation trial has been conducted in patients with advanced PCa, showing that cabozantinib has clinical efficacy in men with CRPC [ 37 ].…”