A phase I, open-label, nonrandomized trial of OPB-31121, a STAT3 inhibitor, in patients with advanced solid tumors.

Oh, D. Alexander; Han, Sheng; Kim, T. M.; Lee, S.; Kim, T.; Heo, Dae-Seog; Bang, Y.

doi:10.1200/jco.2010.28.15_suppl.e13056

Cited by 8 publications

(5 citation statements)

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“…In fact, the dose-limiting toxicity of this compound did not show hematological toxicity in phase I trial with a maximum dose of 800 mg/kg. 29 No hematological toxicity was observed in the toxicity study of this compound in monkeys (1000 mg/kg for 14 days, data not shown). Although the importance of STAT3 and STAT5 in various signals from cytokines such as erythropoietin, thrombopoietin and granulocyte-colony stimulating factor has been established, the dependence on STAT signaling will be lower in normal hematopoietic cells than in malignant cells.…”

Section: Discussionmentioning

confidence: 91%

A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases

Hayakawa

Sugimoto

Harada

et al. 2013

Blood Cancer Journal

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Signal transduction and activator of transcription (STAT) proteins are extracellular ligand-responsive transcription factors that mediate cell proliferation, apoptosis, differentiation, development and the immune response. Aberrant signals of STAT induce uncontrolled cell proliferation and apoptosis resistance and are strongly involved in cancer. STAT has been identified as a promising target for antitumor drugs, but to date most trials have not been successful. Here, we demonstrated that a novel STAT inhibitor, OPB-31121, strongly inhibited STAT3 and STAT5 phosphorylation without upstream kinase inhibition, and induced significant growth inhibition in various hematopoietic malignant cells. Investigation of various cell lines suggested that OPB-31121 is particularly effective against multiple myeloma, Burkitt lymphoma and leukemia harboring BCR–ABL, FLT3/ITD and JAK2 V617F, oncokinases with their oncogenicities dependent on STAT3/5. Using an immunodeficient mouse transplantation system, we showed the significant antitumor effect of OPB-31121 against primary human leukemia cells harboring these aberrant kinases and its safety for normal human cord blood cells. Finally, we demonstrated a model to overcome drug resistance to upstream kinase inhibitors with a STAT inhibitor. These results suggested that OPB-31121 is a promising antitumor drug. Phase I trials have been performed in Korea and Hong Kong, and a phase I/II trial is underway in Japan.

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Section: Discussionmentioning

confidence: 91%

A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases

Hayakawa

Sugimoto

Harada

et al. 2013

Blood Cancer Journal

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“…Small-molecule downstream pathway inhibitors directed towards inhibition of STAT3 phosphorylation showed preliminary tolerability in a phase I trial of advanced solid tumors, but data are not yet available for HCC [76]. …”

Section: Pharmacologic Cmet Inhibitorsmentioning

confidence: 99%

Targeting the HGF-cMET Axis in Hepatocellular Carcinoma

Venepalli

Goff

2013

International Journal of Hepatology

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Under normal physiological conditions, the hepatocyte growth factor (HGF) and its receptor, the MET transmembrane tyrosine kinase (cMET), are involved in embryogenesis, morphogenesis, and wound healing. The HGF-cMET axis promotes cell survival, proliferation, migration, and invasion via modulation of epithelial-mesenchymal interactions. Hepatocellular cancer (HCC) is the third most common cause of worldwide cancer-related mortality; advanced disease is associated with a paucity of therapeutic options and a five-year survival rate of only 10%. Dysregulation of the HGF-cMET pathway is implicated in HCC carcinogenesis and progression through activation of multiple signaling pathways; therefore, cMET inhibition is a promising therapeutic strategy for HCC treatment. The authors review HGF-cMET structure and function in normal tissue and in HCC, cMET inhibition in HCC, and future strategies for biomarker identification.

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“…[59][60][61][62][63] More interestingly, data from preclinical studies suggest that the modality of HGF/MET activation, such as autocrine/ paracrine stimulation, gene amplification, or mutation, is crucial to be able to predict the class of agents that can effectively interrupt the signaling pathway. A list of anti-MET agents currently under investigation in NSCLC clinical trials is shown in Table 1.…”

Section: -61mentioning

confidence: 99%

“…117,118 Downstream signaling pathway OPB-31121 is a small molecule that inhibits interleukin-6-induced phosphorylation of STAT3, leading to disruption of the JAK/STAT signaling pathway. 63 In a Phase I doseescalation study in patients with advanced solid tumors, including lung cancer, OPB-31121 produced disease stabilization in 47% of cases, with a favorable toxicity profile. 63 The promising antitumor activity of this compound warrants further investigation.…”

Section: Non-selective Inhibitorsmentioning

confidence: 99%

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MET overexpression and gene amplification in NSCLC: a clinical perspective

Landi

Minuti

D’Incecco

et al. 2013

LCTT

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Abstract:The transmembrane tyrosine kinase mesenchymal-epidermal transition (MET) receptor and its ligand, hepatocyte growth factor, also known as scatter factor, have recently been identified as novel promising targets in several human malignancies, including non-small cell lung cancer (NSCLC). Amplification, mutation, or overexpression of the MET gene can result in aberrant activation of the MET axis, leading to migration, invasion, proliferation, metastasis, and neoangiogenesis of cancer cells, suggesting that interfering with the MET/hepatocyte growth factor pathway could represent a potential antitumor strategy. While the role of MET mutations in NSCLC is not as yet fully understood, retrospective studies have shown that an increased MET gene copy number is a negative prognostic factor. In NSCLC, amplification of the MET gene is a relatively rare event, occurring in approximately 4% of patients not previously exposed to systemic therapies and in up to 20% of patients with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. In preclinical models, the presence of MET amplification is a predictor of high sensitivity to anti-MET compounds, and several agents have entered in clinical trials for patients having advanced disease, with promising results. The aim of the present review is to summarize available data on the role of MET in NSCLC and to describe therapeutic strategies under investigation.

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A phase I, open-label, nonrandomized trial of OPB-31121, a STAT3 inhibitor, in patients with advanced solid tumors.

Cited by 8 publications

References 0 publications

A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases

A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases

Targeting the HGF-cMET Axis in Hepatocellular Carcinoma

MET overexpression and gene amplification in NSCLC: a clinical perspective

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