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Published on: April 24, 2016
Therapeutic Intervention Using a Smad7-Based Tat Protein to Treat Radiation-Induced Oral Mucositis
Mary-Keara Boss1, Yao Ke2, Li Bian3
1Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado.
Purpose:
Recent studies reported therapeutic effects of Smad7 on oral mucositis in mice without compromising radiation therapy-induced cancer cell killing in neighboring oral cancer. This study aims to assess whether a Smad7-based biologic can treat oral mucositis in a clinically relevant setting by establishing an oral mucositis model in dogs and analyzing molecular targets.
Methods And Materials:
We created a truncated human Smad7 protein fused with the cell-penetrating Tat tag (Tat-PYC-Smad7). We used intensity modulated radiation therapy to induce oral mucositis in dogs and applied Tat-PYC-Smad7 to the oral mucosa in dose-finding studies after intensity modulated radiation therapy. Clinical outcomes were evaluated. Molecular targets were analyzed in biopsies and serum samples.
Results:
Tat-PYC-Smad7 treatment significantly shortened the duration of grade 3 oral mucositis based on double-blinded Veterinary Radiation Therapy Oncology Group scores and histopathology evaluations. Topically applied Tat-PYC-Smad7 primarily penetrated epithelial cells and was undetectable in serum. NanoString nCounter Canine IO Panel identified that, compared to the vehicle samples, top molecular changes in Tat-PYC-Smad7 treated samples include reductions in inflammation and cell death and increases in cell growth and DNA repair. Consistently, immunostaining shows that Tat-PYC-Smad7 reduced DNA damage and neutrophil infiltration with attenuated TGF-β and NFκB signaling. Furthermore, IL-1β and TNF-α were lower in Tat-PYC-Smad7 treated mucosa and serum samples compared to those in vehicle controls.
Conclusions:
Topical Tat-PYC-Smad7 application demonstrated therapeutic effects on oral mucositis induced by intensity modulated radiation therapy in dogs. The local effects of Tat-PYC-Smad7 targeted molecules involved in oral mucositis pathogenesis as well as reduced systemic inflammatory cytokines.
Insights
A novel Smad7 biologic effectively treated radiation-induced oral mucositis in dogs, reducing inflammation and promoting healing. This Smad7 therapy offers a promising treatment for oral mucositis without impacting cancer treatment efficacy.
Area of Science:
- Oncology
- Translational Medicine
- Biotechnology
Background:
- Oral mucositis (OM) is a debilitating side effect of radiation therapy (RT).
- Smad7 has shown therapeutic potential in preclinical models of OM.
- A clinically relevant canine model is needed to evaluate Smad7-based therapies.
Purpose of the Study:
- To assess the efficacy of a Smad7-based biologic in treating radiation-induced oral mucositis in a canine model.
- To analyze the molecular targets and systemic effects of the Smad7 biologic.
Main Methods:
- A truncated human Smad7 protein fused with a cell-penetrating Tat tag (Tat-PYC-Smad7) was developed.
- Oral mucositis was induced in dogs using intensity modulated radiation therapy (IMRT).
- Tat-PYC-Smad7 was topically applied, and clinical outcomes, molecular targets in biopsies, and serum samples were analyzed.
Main Results:
- Tat-PYC-Smad7 significantly reduced the duration of severe oral mucositis.
- The treatment reduced inflammation, cell death, DNA damage, and neutrophil infiltration.
- Key signaling pathways (TGF-β, NFκB) and inflammatory cytokines (IL-1β, TNF-α) were attenuated.
Conclusions:
- Topical Tat-PYC-Smad7 is therapeutically effective for radiation-induced oral mucositis in dogs.
- The Smad7 biologic acts locally to target OM pathogenesis and reduce systemic inflammation.
