Radio-protection of the salivary gland

描述（申请人提供）：唾液腺功能减退是头颈癌放疗的常见并发症，降低了抗癌治疗的有效性和受影响患者的生活质量。我们之前的研究表明PKC？是由辐照和其他DNA损伤剂诱导的唾液腺凋亡的关键调节因子。此外，我们已经证明了PKC？体外，还是基因消融的PKC？在体内，可以保护唾液腺免受辐射引起的损伤。重要的是，我们已经阐明了PKC？调节唾液上皮细胞凋亡的功能，并确定了该过程中可以靶向治疗的关键步骤。具体来说，我们已经证明酪氨酸磷酸化启动PKC？，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持唾液腺功能。许多酪氨酸激酶抑制剂（TKIs）被FDA批准用于癌症治疗；因此，这些药物有可能很快进入临床，用于接受放射治疗的患者。同样，PKC？用于治疗癌症的药物，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。这里我们将研究PKC的tki和SMIs。对放疗或放疗+化疗的头颈癌患者涎腺功能的保护作用。我们还将确定这些药物是否会影响头颈癌小鼠模型的肿瘤治疗。我们的研究可能会对面临涎腺功能丧失前景的头颈癌患者的口腔健康和生活质量产生迅速而深远的影响。

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.