Radio-protection of the salivary gland

描述（由申请方提供）：唾液腺功能减退是头颈癌放射治疗的常见并发症，会降低抗癌治疗的有效性和受影响患者的生活质量。我们以前的研究表明，PKC？是辐射和其他DNA损伤剂诱导的唾液腺细胞凋亡的关键调节剂。 此外，我们已经表明，PKC？在体外，或基因消融的PKC？在体内，可以保护唾液腺免受辐射诱导的损伤。重要的是，我们已经阐明了如何PKC？功能调节唾液上皮细胞的凋亡，并确定了这一过程中的关键步骤，可以有针对性的治疗。具体来说，我们已经证明酪氨酸磷酸化通过PKC？启动促凋亡信号，导致其核积累。 我们假设，在头颈部照射的情况下，抑制介导这一步骤的酪氨酸激酶可能会抑制细胞凋亡并保护唾液腺功能。许多酪氨酸激酶抑制剂（TKI）被FDA批准用于癌症治疗;因此，这些药物可能会迅速过渡到临床，用于接受放射治疗的患者。同样，PKC？的小分子抑制剂（SMI），在开发用于治疗癌症时，也是对接受放射治疗的唾液腺患者进行预防性保护的合理选择。在这里，我们将调查TKI和SMI的PKC？在接受放疗或放疗+化疗的头颈癌患者中保护唾液腺功能的能力。 我们还将使用头颈癌的正交各向异性小鼠模型来确定这些药物是否影响肿瘤治疗。 我们的研究可能对诊断为头颈癌的患者的口腔健康和生活质量产生快速而深远的影响，这些患者面临着唾液腺功能丧失的前景。

DESCRIPTION (provided by applicant): 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.