Early Clinical Development of ARQ 197, a Selective, Non–ATP-Competitive Inhibitor Targeting MET Tyrosine Kinase for the Treatment of Advanced Cancers

Adjei, Alex A.; Schwartz, Brian; Garmey, Edward G.

doi:10.1634/theoncologist.2010-0380

Cited by 66 publications

(56 citation statements)

References 34 publications

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“…Given the importance and the potential therapeutic role of the c-MET receptor in bone metastasis progression, we examined the effects of inhibiting c-MET using both a specific c-MET inhibitor (tivantinib) and RNA interference technology in an in vivo murine model of breast cancer bone metastasis (17). Tivantinib is a novel, orally available, small-molecule, non-ATP-competitive c-MET inhibitor that is highly specific for the c-MET receptor (18)(19)(20)(21). Here we show that treatment with different concentrations of tivantinib affected bone metastasis progression in a dose-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown

Previdi

Abbadessa

Dalò

et al. 2012

Molecular Cancer Therapeutics

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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. Mol Cancer Ther; 11(1); 214-23. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown

Previdi

Abbadessa

Dalò

et al. 2012

Molecular Cancer Therapeutics

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“…41) A phase I study was recently completed with 28 Japanese HCC patients who failed with sorafenib, to evaluate the safety, tolerability, and pharmacokinetics of oral tivantinib as a single agent. As a result, it was found that 120 mg twice daily (BID) of tivantinib could be recommended for HCC patients regardless of CYP2C19 phenotype.…”

mentioning

confidence: 99%

Molecular Targeted Therapy for Hepatocellular Carcinoma: Present Status and Future Directions

Choi

Baik

et al. 2015

Biological & Pharmaceutical Bulletin

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Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most lethal neoplasm, causing an estimated 700000 deaths annually. Currently HCC has only one systemic molecular targeted therapy, the multi-kinase inhibitor, sorafenib. The standard-of-care for advanced liver cancer is limited because sorafenib can expand the median life expectancy of patients for only 1 year. Thus there is an urgent need to develop a novel molecular targeted therapy to improve therapeutic outcomes for HCC. HCCs are phenotypically and genetically heterogeneous tumors driven by diverse molecular mechanisms. However, HCCs exhibit certain common traits selected through genetic and epigenetic alterations. The identification of common molecular alterations may provide an opportunity to develop more effective anticancer treatment through targeted therapy. Recent studies in liver cancer biology have revealed a limited number of molecular targets responsible for initiating and maintaining dysregulated cell proliferation, including vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptor (PDGFR), c-mesenchymal-epithelial transition factor-1 (c-Met), mammalian target of rapamycin (mTOR) and histone deacetylases (HDACs). New treatments involving inhibitors targeting several of these critical pathways are in development. This review describes the current understanding of target pathways, ongoing clinical trials using HCC-targeted agents, and future directions in the treatment of HCC.

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“…Tivantinib is a selective oral inhibitor of c-MET (50). A randomized phase II trial in patients with advanced HCC who failed sorafenib treatment showed a statistically significant improvement in TTP in the Tivantinib group vs. placebo (1.6 vs. 1.4 months; HR 0.64; 90% CI, 0.43-0.94; P=0.04).…”

Section: C-met: Tivantinibmentioning

confidence: 99%

Systemic therapy for advanced hepatocellular carcinoma: an update

Desai¹,

Ochoa²,

Prins³

et al. 2017

J. Gastrointest. Oncol.

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Early Clinical Development of ARQ 197, a Selective, Non–ATP-Competitive Inhibitor Targeting MET Tyrosine Kinase for the Treatment of Advanced Cancers

Abstract: ABSTRACT

Cited by 66 publications

References 34 publications

Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown

Breast Cancer–Derived Bone Metastasis Can Be Effectively Reduced through Specific c-MET Inhibitor Tivantinib (ARQ 197) and shRNA c-MET Knockdown

Molecular Targeted Therapy for Hepatocellular Carcinoma: Present Status and Future Directions

Systemic therapy for advanced hepatocellular carcinoma: an update

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