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.