Abstract
Radiotherapy of head and neck cancers often results in collateral damage to adjacent salivary glands associated with clinically significant hyposalivation and xerostomia. Due to the reduced capacity of salivary glands to regenerate, hyposalivation is treated by substitution with artificial saliva, rather than through functional restoration of the glands. During embryogenesis, the ectodysplasin/ectodysplasin receptor (EDA/EDAR) signaling pathway is a critical element in the development and growth of salivary glands. We have assessed the effects of pharmacological activation of this pathway in a mouse model of radiation-induced salivary gland dysfunction. We report that post-irradiation administration of an EDAR-agonist monoclonal antibody (mAbEDAR1) normalizes function of radiation damaged adult salivary glands as determined by stimulated salivary flow rates. In addition, salivary gland structure and homeostasis is restored to pre-irradiation levels. These results suggest that transient activation of pathways involved in salivary gland development could facilitate regeneration and restoration of function following damage.
Highlights
40,000 new cases of head and neck cancer are diagnosed each year in the United States with five year survival rates around 64% [1]
There are few approved therapies that can substantially improve the quality of life for these individuals [3]. In this preclinical study we have investigated a new therapeutic for its potential use in restoring salivary gland function following radiotherapy
Utilization of mAbEDAR1 in animals with radiation-induced loss of function led to an improvement in physiological function of the salivary glands at day 14 and a complete restoration of function by day 30 (Figure 2)
Summary
40,000 new cases of head and neck cancer are diagnosed each year in the United States with five year survival rates around 64% [1]. Treatment for head and neck cancer typically involves surgical resection with subsequent radiation or chemoradiation therapy [2]. These necessary but tissue-nonspecific treatment modalities are associated with inadvertent and often clinically significant damage to surrounding normal tissues. Salivary glands in close proximity to the tumor exhibit both acute and chronic responses to radiation damage. A number of tissue pathologies have been reported in irradiated salivary glands including loss of acinar cells, focal inflammation, atrophy, vacuolization, and fibrosis [4]. As a result there are a significant number of patients who have completed their treatment regimen that continue to suffer from these side effects [6]. The currently available xerostomia treatment options are palliative at best and are not considered a long-term solution [3]
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