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Updated: Jun 16, 2026
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Published on: April 22, 2019
Efficacy of combining GMX1777 with radiation therapy for human head and neck carcinoma
Hisayuki Kato1, Emma Ito, Wei Shi
1Department of Medical Biophysics, University of Toronto, Toronto, Canada.
Purpose:
Rapidly metabolizing tumor cells have elevated levels of nicotinamide phosphoribosyltransferase, an enzyme involved in NAD(+) biosynthesis, which serves as an important substrate for proteins involved in DNA repair. GMX1777, which inhibits nicotinamide phosphoribosyltransferase, was evaluated in two human head and neck cancer models in combination with radiotherapy.
Experimental Design:
Effects of GMX1777-mediated radiosensitization were examined via metabolic and cytotoxicity assays in vitro; mechanism of action, in vivo antitumor efficacy, and radiosensitization were also investigated.
Results:
IC(50) values of GMX1777 for FaDu and C666-1 cells were 10 and 5 nmol/L, respectively, which interacted synergistically with radiotherapy. GMX1777 induced a rapid decline in intracellular NAD(+) followed by ATP reduction associated with significant cytotoxicity. These metabolic changes were slightly increased with the addition of radiotherapy, although poly(ADP-ribose) polymerase activity was significantly reduced when GMX1777 was combined with radiotherapy, thereby accounting for the synergistic cytotoxicity of these two modalities. Systemic GMX1777 administration with local tumor radiotherapy caused complete disappearance of FaDu and C666-1 tumors for 50 and 20 days, respectively. There was also significant reduction in tumor vascularity, particularly for the more sensitive FaDu model. [(18)F]FDG-positron emission tomography/computed tomography images showed reduction in [(18)F]FDG uptake after GMX1777 administration, showing decreased glucose metabolism in vivo.
Conclusions:
Our data represent the first report showing that GMX1777 plus radiotherapy is an effective therapeutic strategy for head and neck cancer, mediated via pleiotropic effects of inhibition of DNA repair and tumor angiogenesis, while sparing normal tissues. Therefore, GMX1777 combined with radiotherapy definitely warrants clinical evaluation in human head and neck cancer patients.
Insights
GMX1777 combined with radiotherapy effectively treats head and neck cancer by inhibiting DNA repair and angiogenesis. This combination therapy shows significant tumor reduction and warrants clinical trials.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Head and neck cancers exhibit elevated nicotinamide phosphoribosyltransferase (NAMPT), crucial for NAD(+) biosynthesis and DNA repair.
- NAD(+) is a vital substrate for DNA repair proteins, making NAMPT a potential therapeutic target.
Purpose of the Study:
- To evaluate GMX1777, a NAMPT inhibitor, in combination with radiotherapy for head and neck cancer.
- To investigate the radiosensitizing effects and underlying mechanisms of GMX1777.
Main Methods:
- In vitro metabolic and cytotoxicity assays were performed.
- In vivo antitumor efficacy and radiosensitization were assessed in human head and neck cancer models.
- Mechanism of action studies included NAD(+) and ATP levels, and poly(ADP-ribose) polymerase activity.
Main Results:
- GMX1777 demonstrated synergistic cytotoxicity with radiotherapy in FaDu and C666-1 cells (IC50 values 10 and 5 nmol/L).
- GMX1777 caused rapid NAD(+) and ATP depletion, significantly reduced poly(ADP-ribose) polymerase activity, and led to complete tumor regression in vivo.
- Combined treatment reduced tumor vascularity and glucose metabolism, as evidenced by decreased [(18)F]FDG uptake.
Conclusions:
- GMX1777 plus radiotherapy is a promising therapeutic strategy for head and neck cancer.
- The combination therapy exerts pleiotropic effects, inhibiting DNA repair and tumor angiogenesis.
- Clinical evaluation of GMX1777 with radiotherapy in human head and neck cancer patients is warranted.
