Phase I trial with a novel oral NF-κB/STAT3 inhibitor RTA 402 in patients with solid tumors and lymphoid malignancies

Hong, Dae-Eui; Kurzrock, Razelle; Supko, Jeffrey G.; Lawrence, Donald P.; Wheler, J. J.; Meyer, Christoph; Mier, Juan; Andreeff, M.; Shapiro, G.; Dezube, Bruce J.

doi:10.1200/jco.2008.26.15_suppl.3517

Cited by 18 publications

(14 citation statements)

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“…[49][50][51] Thus, STAT3 may be a promising target for therapy as initial phase I clinical trials suggest tolerable toxicity and inhibition of STAT3 activity in vivo associated with responses in solid tumors (including three melanomas) and lymphoid malignancies. 52 Interestingly, recent system biology analysis of phosphoproteomic changes in B-RAF V600E mutant melanoma cell lines implicated STAT3 activation as central to vemurafenib resistance of melanoma cells 53 suggesting that re-establishment of STAT3 activity may have a critical step in MAPK inhibitor resistance, and this indicates that combination of STAT3 and MAPK inhibitors may be an effective second-line therapy.…”

Section: Discussionmentioning

confidence: 99%

Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor

et al. 2013

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Approximately 50% of melanomas depend on mutant B-RAF for proliferation, metastasis and survival. The inhibition of oncogenic B-RAF with highly targeted compounds has produced remarkable albeit short-lived clinical responses in B-RAF mutant melanoma patients. Reactivation of signaling downstream of B-RAF is frequently associated with acquired resistance to B-RAF inhibitors, and the identification of B-RAF targets may provide new strategies for managing melanoma. Oncogenic B-RAF(V600E) is known to promote the stabilizing phosphorylation of the anti-apoptotic protein Mcl-1, implicated in melanoma survival and chemoresistance. We now show that B-RAF(V600E) signaling also induces the transcription of Mcl-1 in melanocytes and melanoma. We demonstrate that activation of STAT3 serine-727 and tyrosine-705 phosphorylations is promoted by B-RAF(V600E) activity and that the Mcl-1 promoter is dependent on a STAT consensus-site for B-RAF-mediated activation. Consequently, suppression of STAT3 activity disrupted B-RAF(V600E)-mediated induction of Mcl-1 and reduced melanoma cell survival. We propose that STAT3 has a central role in the survival and contributes to chemoresistance of B-RAF(V600E) melanoma.

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Section: Discussionmentioning

confidence: 99%

Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor

et al. 2013

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“…Notably, phase I clinical trials of this oral agent are currently ongoing at The University of Texas M. D. Anderson Cancer Center in patients with solid tumors, with first indications of clinical activity and notable lack of toxicity, particularly any cardiotoxicity (45). The elucidation of the mechanism of CDDO-Me-induced cell killing will provide useful information to optimize antileukemic strategies targeting CML (especially among refractory cases) in upcoming clinical trials using this novel triterpenoid.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mitochondrial metabolism by methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate induces apoptotic or autophagic cell death in chronic myeloid leukemia cells

Samudio¹,

Kurinna

Ruvolo

et al. 2008

Molecular Cancer Therapeutics

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The initial success of the first synthetic bcr-abl kinase inhibitor imatinib has been dampened by the emergence of imatinib-resistant disease in blast crisis chronic myeloid leukemia. Here, we report that the novel triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate (CDDO-Me) potently induced cytotoxicity in imatinibresistant KBM5 cells expressing the T315I mutation of bcr-abl (24-h EC 50 , 540 nmol/L). In long-term culture, CDDO-Me abrogated the growth of human parental KBM5 and KBM5-STI cells with 96-h IC 50 of 205 and 221 nmol/L, respectively. In addition, CDDO-Me rapidly decreased the viability of murine lymphoid Ba/F3 cells expressing wild-type p210 as well as the imatinib-resistant E255K and T315I mutations of bcr-abl. The low-dose effects of CDDO-Me are associated with inhibition of mitochondrial oxygen consumption, whereas the cytotoxic effects appear to be mediated by a rapid and selective depletion of mitochondrial glutathione that accompanies the increased generation of reactive oxygen species and mitochondrial dysfunction. Interestingly, the mitochondriotoxic effects of CDDO-Me are followed by the rapid autophagocytosis of intracellular organelles or the externalization of phosphatidylserine in different cell types. We conclude that alterations in mitochondrial function by CDDO-Me can result in autophagy or apoptosis of chronic myeloid leukemia cells regardless of the mutational status of bcr-abl. CDDO-Me is in clinical trials and shows signs of clinical activity, with minimal side effects and complete lack of cardiotoxicity. Studies in leukemias are in preparation. [Mol Cancer Ther 2008;7(5):1130 -9]

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“…Bardoxolone methyl was well tolerated; 91% of patients had minimal toxicities (Ͻ grade 2) even when administered for up to 1 year, and a dose of 900 mg/day was set for phase 2 studies. Of 30 assessable patients in the second study, 40% achieved disease stabilization and two objective responses were seen (Hong et al, 2008). The results of this phase 1 study have been published (Hong et al, 2012).…”

Section: Clinical Activitymentioning

confidence: 91%

“…Interim results from dose-escalation studies with bardoxolone methyl (http://clinicaltrials.gov/ct2/ show/NCT00508807) in 34 or 47 patients with advanced, refractory solid tumors or lymphoid malignancies have been presented (Dezube et al, 2007;Hong et al, 2008). The drug was administered orally for 21 of every 28 days at doses from 5 to 1300 mg/day.…”

Section: Clinical Activitymentioning

confidence: 99%