Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors

Bendell, Johanna C.; Hong, David S.; Burris, Howard A.; Naing, Aung; Jones, Suzanne F.; Falchook, Gerald S.; Bricmont, Patricia; Elekes, Agnes; Rock, Edwin P.; Kurzrock, Razelle

doi:10.1007/s00280-014-2480-2

Cited by 95 publications

(70 citation statements)

References 8 publications

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“…STAT3 activation in other patients may be a result of genetic mutations or epigenetic changes in other components of the Janus kinase (JAK)-STAT pathway. Importantly, these results collectively suggest that JAK-STAT inhibitors, such as the JAK inhibitors and STAT3 inhibitors currently in clinical trials, 16 may be an effective treatment of L-HES.…”

Section: Cd4mentioning

confidence: 80%

Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome

Walker

Wang

Walradt

et al. 2016

Blood

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Section: Cd4mentioning

confidence: 80%

Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome

Walker

Wang

Walradt

et al. 2016

Blood

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“…To date, small-molecule STAT3i have shown relevant activity in preclinical models and few of them are currently investigated in clinical trials (11,(13)(14)(15)(16)(17). However, an important gap persists in our knowledge of the biological mechanisms of antitumor activity, the critical cellular processes affected, and the factors determining sensitivity of cancer cells to STAT3i, hindering further clinical development of these highly promising anticancer drugs.…”

Section: Opb-51602mentioning

confidence: 99%

Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

Genini

Brambilla

Laurini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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In addition to its canonical role in nuclear transcription, signal transducer and activator of transcription 3 (STAT3) is emerging as an important regulator of mitochondrial function. Here, we demonstrate that a novel inhibitor that binds with high affinity to the STAT3 SH2 domain triggers a complex cascade of events initiated by interference with mitochondrial STAT3 (mSTAT3). The mSTAT3-drug interaction leads to mitochondrial dysfunction, accumulation of proteotoxic STAT3 aggregates, and cell death. The cytotoxic effects depend directly on the drug's ability to interfere with mSTAT3 and mitochondrial function, as demonstrated by site-directed mutagenesis and use of STAT3 knockout and mitochondria-depleted cells. Importantly, the lethal consequences of mSTAT3 inhibition are enhanced by glucose starvation and by increased reliance of cancer cells and tumor-initiating cells on mitochondria, resulting in potent activity in cell cultures and tumor xenografts in mice. These findings can be exploited for eliciting synthetic lethality in metabolically stressed cancer cells using highaffinity STAT3 inhibitors. Thus, this study provides insights on the role of mSTAT3 in cancer cells and a conceptual framework for developing more effective cancer therapies.S ignal transducer and activator of transcription 3 (STAT3) is a key element in multiple signaling pathways and is aberrantly activated in many human cancers (1, 2). STAT3 promotes cell proliferation, survival, angiogenesis, and immune-evasion (1-3). Phosphorylation at Tyr705 (pTyr705), catalyzed by Janus kinases (JAK) and other tyrosine kinases, induces STAT3 dimerization through the interaction of the SH2 domain (SH2D), nuclear accumulation, and target gene transcription (1, 3, 4). Emerging evidence indicates that STAT3 also localizes to mitochondria and controls mitochondrial functions (2, 5-7). Mitochondrial localized STAT3 (mSTAT3) is critical for survival of RAStransformed mouse embryo fibroblasts (MEF) under glucosestarvation, reflecting a specific dependency of cancer cells on mitochondria in certain conditions (6). Interestingly, mSTAT3 is prevalently phosphorylated at Ser727 (pSer727), which enhances its mitochondrial functions (5, 6). Furthermore, constitutive pSer727 is found in many human cancers and is apparently sufficient to drive tumorigenesis in various model systems (8-10).STAT3 is an attractive cancer therapeutic target because of its central role in multiple oncogenic processes and great effort has been devoted in recent years to discover STAT3 inhibitors (STAT3i) (11,12). To date, small-molecule STAT3i have shown relevant activity in preclinical models and few of them are currently investigated in clinical trials (11,(13)(14)(15)(16)(17). However, an important gap persists in our knowledge of the biological mechanisms of antitumor activity, the critical cellular processes affected, and the factors determining sensitivity of cancer cells to STAT3i, hindering further clinical development of these highly promising anticancer drugs. Indeed, great atten...

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“…Moreover, it has been attempted to inhibit STAT3 by RNA interference locally within the tumor (22) or by injecting small inhibitors that interfere with the transactivation of STAT3 target genes (23,24). Phase I trials involving small STAT3 inhibitors have been initiated in cancer patients (25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells

et al. 2015

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STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice.

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Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors

Abstract: Twice-daily administration of OPB-31121 was feasible up to doses of 300 mg. The pharmacokinetic profile was unfavorable, and no objective responses were observed.

Cited by 95 publications

References 8 publications

Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome

Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome

Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells

STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells

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