The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations

Geiger, J.L.; Grandis, Jennifer R.; Bauman, Julie E.

doi:10.1016/j.oraloncology.2015.11.022

Cited by 154 publications

(126 citation statements)

References 138 publications

(131 reference statements)

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“…Signal transducer and activator of transcription 3 (STAT3) has been implicated in most cancer types including head and neck cancer [1–6]. Head and neck squamous cell carcinoma (HNSCC) accounts for 90% of diagnosed head and neck cancers.…”

Section: Introductionmentioning

confidence: 99%

“…STAT3 has been found to be constitutively active in HNSCC cell lines and tumors [1,6]. Aberrant STAT3 activation can lead to the initiation, development and metastasis of cancers by misregulating the genes and proteins needed to overcome cancerous progression barriers [3,9,10, 5, 1].…”

Section: Introductionmentioning

confidence: 99%

“…Aberrant STAT3 activation can lead to the initiation, development and metastasis of cancers by misregulating the genes and proteins needed to overcome cancerous progression barriers [3,9,10, 5, 1]. STAT3 activation has been labeled an oncogene and can lead to the initiation, development and metastasis in cancer by regulating functions such as cellular proliferation, cell cycle progression, apoptosis, angiogenesis, immune invasion, survival, inflammation, invasion and metastasis [3,1,4,9,11,12]. The role of STAT3 as a point of convergence for multiple cancerous pathways has made it an attractive target for the development of new chemotherapeutic therapies.…”

Section: Introductionmentioning

confidence: 99%

“…STAT3 is part of a seven member protein family that are structurally similar and act as cytosolic signal transducers and transcription factors that regulate gene transcription [1,4,13,5]. The member STAT1 acts a tumor suppressor and this function should be preserved [4,14].…”

Section: Introductionmentioning

confidence: 99%

“…The member STAT1 acts a tumor suppressor and this function should be preserved [4,14]. A growing body of evidence has implicated IL-6 as a prominent activator of STAT3 in HNSCC [6,1]. Based on three hits identified in a high content screening (HCS) campaign that selectively inhibited IL-6-induced pSTAT3 activation over IFNγ-induced pSTAT1 activation and inhibited HNSCC tumor cell line growth in vitro [15,16], the 1,2,4-triazolo-[3,4-b] thiadiazines were selected for further chemical optimization [17].…”

Section: Introductionmentioning

confidence: 99%

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Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Kiesel

Parise

Guo

et al. 2016

Cancer Chemother Pharmacol

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Purpose The oncogenic transcription factor STAT3 promotes gene transcription involved in cancer and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination. Methods Metabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity. Single dose pharmacokinetics (PK), bioavailability and metabolism were studied after IV 4 mg/kg, PO 4 mg/kg, or PO 30 mg/kg suspension in 1% carboxymethyl cellulose. Mice were euthanized between 5 min to 24 h after dosing and plasma and tissues were analyzed by LC-MS. Non-compartmental PK parameters were determined. Results Of the four triazolothiadizine analogues evaluated, UPCDC-10205 was metabolically most stable. The maximum soluble dose of 4 mg/kg in 10% Solutol™ was not toxic to mice after single and multiple doses. PK analysis showed extensive tissue distribution and rapid plasma clearance. Bioavailability was ~5%. A direct glucuronide conjugate was identified as the major metabolite which was recapitulated in vitro. Conclusions Rapid clearance of UPCDC-10205 was thought to be the result of phase II metabolism despite its favorable stability in a phase I in vitro metabolic stability assay. The direct glucuronidation explains why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability. UPCDC-10205 did not demonstrate appropriate exposure to support efficacy studies in the current formulation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Kiesel

Parise

Guo

et al. 2016

Cancer Chemother Pharmacol

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Deciphering the impact of STAT3 activation mediated by PTPRT promoter hypermethylation as biomarker of response to paclitaxel‐plus‐cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

Cirauqui,

Peguera,

Pi‐Sunyer

et al. 2024

Head & Neck

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BackgroundSquamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor prognosis. It is known that the activation of STAT3 signaling pathways promotes the development and progression of this neoplasia and it has been described the role of PTPRT as a negative regulator of STAT3. Then, we have evaluated the impact of them as biomarkers of outcome in a series of patients with recurrent and/or metastatic SCCHN treated with weekly paclitaxel‐plus‐cetuximab (ERBITAX) regimen.Patients and methodsBetween 2008 and 2017, 52 patients with recurrent/metastatic SCCHN were treated with ERBITAX at our center, 34 of whom had available tumor samples. Phosphorylated STAT3 (pSTAT3) protein expression was analyzed by immunohistochemistry, STAT3 mRNA expression by qPCR, and PTPRT promoter methylation by methylation‐specific PCR. Molecular results were correlated with response rate (RR), progression‐free survival (PFS), and overall survival (OS).ResultspSTAT3 overexpression was detected in 67% and PTPRT promoter hypermethylation in 41% of tumor samples. PTPRT promoter hypermethylation showed a trend towards an association with lower RR (21% vs. 60%; p = 0.06). A lower RR was also observed in patients with pSTAT3 overexpression (36% vs. 54%) and in those with high STAT3 mRNA levels (43% vs. 64%), but these differences did not reach statistical significance. PTPRT promoter hypermethylation correlated with pSTAT3 overexpression (p = 0.009) but not with STAT3 mRNA overexpression. OS and PFS was shorter in patients with activated STAT3, but the difference did not reach statistical significance.ConclusionsAlthough this was a relatively small retrospective study, it provides preliminary indications of the potential role of the STAT3 pathway on outcome in SCCHN and confirms that PTPRT acts as a negative regulator of STAT3. Our findings warrant investigation in a larger patient cohort to determine if inactivating this pathway through specific targeted treatments could improve outcomes in recurrent/metastatic SCCHN patients.

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Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines

Wang

Tang

et al. 2020

IUBMB Life

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Osteosarcoma (OS) is a malignant bone neoplasm, mostly occurring in pediatric patients. OS is characterized by a highly aggressive and metastatically active tumor. Chemotherapy followed by surgical excision is the treatment of choice but is often associated with both chemoresistance and relapse. Hence, it is important to develop further understanding of OS pathogenesis and identify potential therapeutic targets. Both the signal transducer and activator of transcription 3 (STAT3) and mammalian target of rapamycin (mTOR) have been implicated in OS pathogenesis. Crosstalk between mTOR and STAT3 signaling has been shown to regulate hypoxia‐induced angiogenesis in other diseases. In this study, we determined using OS cell lines if there is a crosstalk between these two pathways and how that impacts sensitivity to treatment with Rapamycin. OS cell lines exhibited differential sensitivity to mTOR inhibitor Rapamycin. Evaluation of phosphorylated STAT3 showed that in Rapamycin‐sensitive 143B cells, the inhibitor decreased phosphorylation of STAT3 at Y705, but not at S727 whereas, in Rapamycin‐resistant U2OS cells, the inhibitor decreased S727 phosphorylation but not Y705. However, knockdown of STAT3 in U2OS cells made them sensitive to Rapamycin. Immunofluorescence (IF) analysis showed that mTOR is constitutively activated in the 143B cells but is suppressed in the U2OS cells, indicating that this might be their reason for being resistant to Rapamycin. Both cell lines were sensitive to treatment with the STAT3 inhibitor Napabucasin (NP). Treatment with NP inhibited STAT3 activation at Y705 and additionally inhibited mTOR activation, indicating crosstalk between STAT3 and mTOR signaling pathways. Rapamycin could effectively prevent lung metastasis in an orthotropic OS mice model using 143B cells. However, Rapamycin could not inhibit lung metastasis in mice injected with U2OS cells. The STAT3 inhibitor NP attenuated lung metastasis with the U2OS cells. Our results thus established yet undefined crosstalk of STAT3 and mTOR signaling pathways in OS and highlight the possibility of using mTOR inhibitors for treatment in patients with OS.

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The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations

Cited by 154 publications

References 138 publications

Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation

Deciphering the impact of STAT3 activation mediated by PTPRT promoter hypermethylation as biomarker of response to paclitaxel‐plus‐cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck

Role of crosstalk between STAT3 and mTOR signaling in driving sensitivity to chemotherapy in osteosarcoma cell lines

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