tas-115 and Bone-Neoplasms

TAS-115 is an oral multikinase inhibitor targeting the MET proto-oncogene, vascular endothelial growth factor receptor, and colony-stimulating factor 1 receptor. We evaluated the efficacy and safety of TAS-115 in castration-resistant prostate cancer (CRPC) patients with bone metastases.. This phase II study, conducted in Japan, comprised 2 cohorts of CRPC patients. Cohort A included patients with bone metastasis and no history of docetaxel; TAS-115 200 to 400 mg/d was administered with abiraterone and prednisone. Cohort B included patients with symptomatic multiple bone metastases, post- or unfit for docetaxel, randomized 1:1 to receive TAS-115 400 or 600 mg/d orally, once daily, in a repeated weekly schedule of 5 days on/2 days off. The primary endpoint was bone scan index (BSI) response rate at Week 12 in each dose group.. Cohorts A and B included 24 and 26 patients, respectively. The 12-week BSI response rates for 200, 300, and 400 mg were 0%, 33.3%, and 16.7% in Cohort A, and for 400 and 600 mg were 7.1% and 25.0% in Cohort B. The best BSI response rates for 200, 300, and 400 mg were 0%, 66.7%, and 16.7% in Cohort A, and for 400 and 600 mg were 7.1% and 33.3% in Cohort B. A ≥ 30% reduction in BPI-SF score was shown in 57.7% of patients in Cohort B. The most frequent Grade ≥ 3 adverse drug reactions were hypophosphatemia (20.8%) in Cohort A and anemia (23.1%) in Cohort B.. TAS-115 appears to demonstrate anti-tumor activity and acceptable tolerability in CRPC patients with bone metastases.

Topics: Bone Neoplasms; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Quinolines; Thiourea; Treatment Outcome; Vascular Endothelial Growth Factor A

Osteosarcoma is the most common malignant bone tumor in adolescence and childhood. Metastatic osteosarcoma has a poor prognosis with an overall 5-year survival rate of approximately 20%. TAS-115 is a novel multiple receptor tyrosine kinase inhibitor that is currently undergoing clinical trials. Using the mouse highly lung-metastatic osteosarcoma cell line, LM8, we showed that TAS-115 suppressed the growth of subcutaneous grafted tumor and lung metastasis of osteosarcoma at least partially through the inhibition of platelet-derived growth factor receptor alpha, AXL, and Fms-like tyrosine kinase 3 phosphorylation. We also show that these signaling pathways are activated in various human osteosarcoma cell lines and are involved in proliferation. Our results suggest that TAS-115 may have potential for development into a novel treatment for metastatic osteosarcoma.

Topics: Animals; Axl Receptor Tyrosine Kinase; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; fms-Like Tyrosine Kinase 3; Humans; Lung Neoplasms; Mice; Mice, Inbred C3H; Osteosarcoma; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Quinolines; Receptor Protein-Tyrosine Kinases; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction; Thiourea

The tyrosine kinase inhibitor TAS-115 that blocks VEGF receptor and hepatocyte growth factor receptor MET signaling exhibits antitumor properties in xenografts of human gastric carcinoma. In this study, we have evaluated the efficacy of TAS-115 in preventing prostate cancer metastasis to the bone and bone destruction using the PC3 cell line. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction and subsequent tumor growths were detected. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation by suppressing osteoclastic bone resorption. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption when co-cultured with calvarial bone, but TAS-115 effectively suppressed the PC3-induced bone destruction. We found that macrophage colony-stimulating factor-dependent macrophage differentiation and subsequent receptor activator of NF-κB ligand-induced osteoclast formation were largely suppressed by adding TAS-115. The phosphorylation of the macrophage colony-stimulating factor receptor FMS and osteoclast related kinases such as ERK and Akt were also suppressed by the presence of TAS-115. Gene expression profiling showed that FMS expression was only seen in macrophage and in the osteoclast cell lineage. Our study indicates that tyrosine kinase signaling in host pre-osteoclasts/osteoclasts is critical for bone destruction induced by tumor cells and that targeting of MET/VEGF receptor/FMS activity makes it a promising therapeutic candidate for the treatment of prostate cancer patients with bone metastasis.

Topics: Animals; Bone Neoplasms; Bone Resorption; Cell Differentiation; Cell Line, Tumor; Coculture Techniques; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Nude; Neoplasm Metastasis; Osteoclasts; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-met; Quinolines; Receptor, Macrophage Colony-Stimulating Factor; Receptors, Vascular Endothelial Growth Factor; Thiourea

Approximately 25-40% of patients with lung cancer show bone metastasis. Bone modifying agents reduce skeletal-related events (SREs), but they do not significantly improve overall survival. Therefore, novel therapeutic approaches are urgently required. In this study, we investigated the anti-tumor effect of TAS-115, a VEGFRs and HGF receptor (MET)-targeted kinase inhibitor, in a tumor-induced bone disease model. A549-Luc-BM1 cells, an osteo-tropic clone of luciferase-transfected A549 human lung adenocarcinoma cells (A549-Luc), produced aggressive bone destruction associated with tumor progression after intra-tibial (IT) implantation into mice. TAS-115 significantly reduced IT tumor growth and bone destruction. Histopathological analysis showed a decrease in tumor vessels after TAS-115 treatment, which might be mediated through VEGFRs inhibition. Furthermore, the number of osteoclasts surrounding the tumor was decreased after TAS-115 treatment. In vitro studies demonstrated that TAS-115 inhibited HGF-, VEGF-, and macrophage-colony stimulating factor (M-CSF)-induced signaling pathways in osteoclasts. Moreover, TAS-115 inhibited Feline McDonough Sarcoma oncogene (FMS) kinase, as well as M-CSF and receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation. Thus, VEGFRs/MET/FMS-triple inhibition in osteoclasts might contribute to the potent efficacy of TAS-115. The fact that concomitant dosing of sunitinib (VEGFRs/FMS inhibition) with crizotinib (MET inhibition) exerted comparable inhibitory efficacy for bone destruction to TAS-115 also supports this notion. In conclusion, TAS-115 inhibited tumor growth via VEGFR-kinase blockade, and also suppressed bone destruction possibly through VEGFRs/MET/FMS-kinase inhibition, which resulted in potent efficacy of TAS-115 in an A549-Luc-BM1 bone disease model. Thus, TAS-115 shows promise as a novel therapy for lung cancer patients with bone metastasis.

Topics: A549 Cells; Animals; Bone Neoplasms; Cell Differentiation; Cell Proliferation; Crizotinib; Disease Models, Animal; Humans; Indoles; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Osteoclasts; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrroles; Quinolines; RANK Ligand; Receptor, Macrophage Colony-Stimulating Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sunitinib; Thiourea; Tibia; Transplantation, Heterologous; X-Ray Microtomography