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Published on: October 27, 2020
Targeting TGF beta receptor 1 in head and neck squamous cell carcinoma
Bernhard J Jank1, Julia Schnoell1, Katharina Kladnik1
1Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
Objectives:
The transforming growth factor-Beta (TGF-ß) pathway may be involved in the radioresistance of head and neck squamous cell carcinoma (HNSCC). This study analyzed TGF-ß receptor 1 (TGFBR1) expression in HNSCC patients and evaluated the antineoplastic and radiosensitizing effects of vactosertib, a novel TGFBR1 inhibitor, in vitro.
Materials And Methods:
TGFBR1 expression was examined in HNSCC patients at the mRNA level in silico and the protein level by immunohistochemistry, including surgical specimens of primary tumors, matched lymph node metastasis, and recurrent disease. Furthermore, a novel small molecule TGFBR1 inhibitor was evaluated in HNSCC cell lines. Finally, an indirect coculture model using patient-derived cancer-associated fibroblasts was applied to mimic the tumor microenvironment.
Results:
Patients with high TGFBR1 mRNA levels showed significantly worse overall survival in silico (OS, p = 0.024). At the protein level, an association between TGFBR1+ tumor and OS was observed for the subgroup with TGFBR1-stroma (p = 0.001). Those results prevailed in multivariable analysis. Inhibition of TGFBR1 showed antineoplastic effects in vitro. In combination with radiation, vactosertib showed synergistic effects.
Conclusion:
Our results indicate a high risk of death in tumorTGFBR1+|stromaTGFBR1- expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib.
Insights
High TGFBR1 expression in head and neck cancer correlates with poor survival. Vactosertib, a TGFBR1 inhibitor, shows anti-cancer effects and enhances radiation therapy in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- The transforming growth factor-Beta (TGF-ß) pathway is implicated in head and neck squamous cell carcinoma (HNSCC) radioresistance.
- Targeting TGF-ß signaling is a potential strategy to overcome treatment resistance.
Purpose of the Study:
- To investigate the prognostic significance of TGF-ß receptor 1 (TGFBR1) in HNSCC.
- To evaluate the efficacy of vactosertib, a novel TGFBR1 inhibitor, as an antineoplastic and radiosensitizing agent in HNSCC.
Main Methods:
- TGFBR1 expression analysis (mRNA and protein) in HNSCC patient samples (tumors, lymph nodes, recurrent disease).
- In vitro evaluation of vactosertib in HNSCC cell lines.
- Assessment of vactosertib's effects in combination with radiation using a co-culture model mimicking the tumor microenvironment.
Main Results:
- High TGFBR1 mRNA levels significantly correlated with worse overall survival (OS) in silico.
- TGFBR1 protein expression in tumors, particularly in conjunction with TGFBR1-negative stroma, was associated with poorer OS.
- Vactosertib demonstrated antineoplastic activity in vitro and synergistic radiosensitizing effects when combined with radiation.
Conclusions:
- TGFBR1 expression is a prognostic marker for poor survival in HNSCC patients.
- TGFBR1 inhibition with vactosertib shows promise as a radiosensitizer for HNSCC treatment.
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