Xerostomia (dry mouth) is the most common complication of radiotherapy (RT) in head and neck cancer (HNC). It adversely impacts patients' quality of life and places them at risk for significant late morbidities. Current strategies to mitigate xerostomia are costly and ineffective. Intensity modulated radiotherapy (IMRT), which aims to spare one parotid gland, has resulted in some improvement of stimulatory salivary function, but it cannot spare the SMG glands, which are crucial for resting salivary function throughout the day, because of their locations adjacent to the draining lymph nodes. Recently, we have been able to isolate a highly enriched population of adult salivary stem cells (SSC) from murine submandibular gland (SMG) and showed that as few as 300 cells had the ability restore salivary function when injected into irradiated murine SMG. Gene expression analysis showed that these cells expressed significantly more GNDF than their non-stem-cell counterparts (NSCs) and treatment with a single injection of GDNF either before or after irradiation resulted in enhanced saliva production in GDNF treated mice compared to vehicle controls. Based on these preliminary data, the main objectives of this proposal are: (1) to identify the best dose of GNDF treatment to rescue saliva function, (2) to determine whether GNDF is essential for restoring SMG function after radiation, (3) to determine the mechanism by which GNDF increased SSC survival after radiation, (4) to determine the effect of GDNF treatment on survival and growth of head and neck squamous cell carcinoma (HNSCC), and (5) to identify other genes that may regulate SSC survival and proliferation for future stem cell therapy. Our ultimate goal is to devise novel GNDF or other strategies to mitigate RT-induced xerostomia in HNC patients.
We have found that stem cells exist in the adult saliva glands in mice and these cells can restore saliva function injected into irradiated saliva glands; however, these cells are rare and hard to manipulate. We found that they express high level of GDNF, Neurexin 1, pleotrophin and Drosophila roundabout homolog 2 (Robo2), all of which play an important role in kidney and central nervous system development. We hope that by manipulating the GNDF and these other pathways, we can enhance stem cell survival after radiation and restore saliva function; this will result in novel therapies for radiation-induced dr mouth and its-related complications.
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