Treatment of parathyroid neoplasia by pharmacologic cdk4/6 inhibition

项目总结： 甲状旁腺癌是一种罕见但典型的无法治愈的恶性肿瘤。甲状旁腺激素长期升高 伴发的高钙血症会导致严重的发病率和死亡率。外科手术仍然是主要的 约50%的患者可以看到治疗和复发。精准医学方法可能会改善结果 适用于那些无法通过手术治愈的病人。药理学的CDK4/6抑制剂最近被 介绍了用于治疗各种癌症类型，结果喜忧参半。这些药物可能对 30%的甲状旁腺癌中存在细胞周期蛋白D1扩增。本研究的目的是评估其疗效。 药物CDK4/6抑制剂在细胞周期蛋白D1驱动的甲状旁腺肿瘤小鼠模型中的作用。转基因 小鼠将接受CDK4/6抑制剂Palbociclib或abemaciclib单独或与 Cinacalcet。这些临床前研究将有助于确定药物CDK4/6抑制剂是否可能是 对肿瘤含有Cyclin D1扩增/重排的甲状旁腺癌患者有效， 有可能为无法手术治愈的甲状旁腺癌患者建立一种新的治疗方法。

Project Summary: Parathyroid cancer is a rare, but typically incurable malignancy. Prolonged elevation of parathyroid hormone and accompanying hypercalcemia cause significant morbidity and mortality. Surgery remains the primary treatment and recurrence is seen in ~50% of patients. A precision medicine approach may improve outcomes for patients whose disease is surgically incurable. Pharmacologic cdk4/6 inhibitors have recently been introduced for the treatment of various cancer types, with mixed results. These drugs might be effective in the 30% of parathyroid cancers which harbor cyclin D1 amplification. The aim of this study is to assess the efficacy of pharmacologic cdk4/6 inhibitors in a cyclin D1-driven mouse model of parathyroid neoplasia. Transgenic mice will be treated with the cdk4/6 inhibitors palbociclib or abemaciclib, alone or in combination with cinacalcet. These pre-clinical studies will help to determine if pharmacologic cdk4/6 inhibitors are likely to be effective in parathyroid carcinoma patients whose tumors harbor amplifications/rearrangements of cyclin D1, potentially establishing a new treatment for patients with surgically-incurable parathyroid cancer.