Salivary gland hypofunction is a frequent complication of irradiation for head and neck cancer and diminishes the effectiveness of anti-cancer therapies and the quality of life for affected patients. Our previous studies show that PKC? is a critical regulator of salivary gland apoptosis induced by irradiation and other DNA damaging agents. Moreover, we have shown that depletion of PKC? in vitro, or genetic ablation of PKC? in vivo, can protect the salivary gland from irradiation-induced injury. Importantly, we have elucidated how PKC? functions to regulate apoptosis in salivary epithelial cells, and have identified critical steps in this process that can be targeted therapeutically. Specifically, we have shown that tyrosine phosphorylation initiates pro-apoptotic signaling by PKC?, resulting in its nuclear accumulation. We hypothesize that inhibition of the tyrosine kinases that mediate this step may suppress apoptosis and preserve salivary gland function in the context of head and neck irradiation. Many tyrosine kinase inhibitors (TKIs) are FDA approved for cancer therapy; hence these drugs could potentially be quickly transitioned into the clinic for use in patients receiving radiation therapy. Likewise, small molecule inhibitors (SMIs) of PKC?, in development for treatment of cancer, are also logical choices for prophylactic protection of the salivary gland patients undergoing irradiation. Here we will investigate TKIs and SMIs of PKC? for their ability to protect salivary gland function in head and neck cancer patients undergoing irradiation or irradiation+chemotherapy. We will also determine if these drugs impact tumor therapy using an orthotropic mouse model of head and neck cancer. Our studies may have a rapid and profound impact on the oral health and quality of life of patients diagnosed with head and neck cancer who face the prospect of loss of salivary gland function.

R21DE024309

2014-08-01

2017-01-31