Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal complications associated with significant morbidity and poor prognosis. The cross-talk between ...metastatic cancer cells and bone is critical to the development and progression of bone metastases. We have shown the involvement of the HGF/c-MET system in tumor-bone interaction contributing to human breast cancer metastasis. Therefore, disruption of HGF/c-MET signaling is a potential targeted approach to treating metastatic bone disease. In this study, we evaluated the effects of c-MET inhibition by both an oral, selective, small-molecule c-MET inhibitor, tivantinib, and a specific short hairpin RNA (shRNA) against c-MET in a mouse model of human breast cancer. Tivantinib exhibited dose-dependent antimetastatic activity in vivo, and the 120 mg/kg dose, proven to be suboptimal in reducing subcutaneous tumor growth, induced significant inhibition of metastatic growth of breast cancer cells in bone and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-MET silencing did not affect in vitro proliferation of bone metastatic cells, but significantly reduced their migration, and this effect was further enhanced by tivantinib. Both observations were confirmed in vivo. Indeed, more pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and prolongation of survival were achieved by dual c-MET inhibition using both tivantinib and RNA interference strategies. Overall, our findings highlighted the effectiveness of c-MET inhibition in delaying the onset and progression of bone metastases and strongly suggest that targeting c-MET may have promising therapeutic value in the treatment of bone metastases from breast cancer.
Abstract
Breast cancer exhibits a propensity to metastasize to bone, resulting in debilitating skeletal-related complications associated with significant morbidity and mortality. Because of the ...clinical significance of this process, many research efforts are aimed at uncovering the molecular events in bone metastases to identify novel targets and to improve clinical management of metastatic bone disease. The interactions between metastatic cells and bone are critical to the development and progression of bone metastases, and their unravelling could lead to novel preventive or therapeutic approaches. We previously demonstrated the critical role of HGF/c-Met/β-catenin/TCF system in tumor-bone interaction leading to skeletal metastases of human breast cancer cells, suggesting the potential inhibition of this pathway in vivo. In this study, we evaluated the potential therapeutic efficacy of targeting the c-Met receptor by using both an oral, selective, small-molecule c-Met inhibitor, tivantinib, and a specific shRNA against c-Met in an experimental bone metastatic model of human breast cancer. Tivantinib exhibited dose-dependent anti-metastatic activity in vivo, and the 120 mg/kg dose, while being ineffective in reducing subcutaneous tumor growth, induced significant inhibition of bone metastatic growth and a noteworthy reduction of tumor-induced osteolysis. shRNA-mediated c-Met silencing did not affect in vitro proliferation of bone metastatic cells, but strongly reduced their migration, and this effect was further enhanced by tivantinib. These data were confirmed in vivo. Indeed, dual c-Met inhibition with both tivantinib and RNA interference strategy induces pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and an improvement in survival. Overall, our findings highlighted the efficacy of c-Met inhibition in delaying the onset and progression of bone metastases and strongly suggested that targeting the c-Met receptor may have promising therapeutic value in the prevention and treatment of bone metastases from breast cancer. Most importantly, the finding that tivantinib is active as an anti-metastatic agent at low, non-cytotoxic doses suggests that its efficacy may be potentiated by combining it with other therapies that target cancer cell-bone interactions.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 846. doi:1538-7445.AM2012-846
Venlafaxine (V) is a serotonin-norepinephrine selective reuptake inhibitor, mainly metabolized by cytochrome P4502D6 (CYP2D6). CYP2D6 polymorphisms result in a variety of phenotypes: poor (PMs), ...intermediate (IMs), extensive (EMs), and ultrarapid metabolizers (UMs). PMs usually show poor tolerance to drugs metabolized by CYP2D6, while UMs need greater doses. The aim of this study was to evaluate the impact of CYP2D6 genotype on V dosage, therapeutic response, and side effects in a clinical outpatient setting.
47 patients with Major Depressive Disorder, treated with V 75 - 300 mg/day, underwent CYP2D6 genotyping using the INFINITI-CYP2D6 assay. Duration of treatment and clinical outcome (Clinical Global Impression CGI effectiveness index) were assessed.
CGI assessment was performed after 6 weeks, 6 months, and 1 year of treatment with a V median dose of 150 mg/day. CYP2D6 genotyping resulted in 1 PM, 3 IMs, 42 EMs, and 1 UM. The UM took the greatest V dose (375 mg) without side effects; IMs/PMs took moderate/high doses of V (150 - 300 mg) without adverse effects; EMs displayed high response variability.
PM/IM patients responded to V differently than expected according to genotype. However, the UM patient responded to a dosage higher than the usual therapeutic range and without developing side effects, suggesting an association between CYP2D6 gene duplication and the therapeutic efficacy of venlafaxine. The CYP2D6 genotyping may thus provide clinicians with a potential explanation for those patients requiring greater doses of CYP2D6 substrates in order to obtain the same therapeutic efficacy.
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