Efficacy of cyclin-dependent kinase 4/6 inhibitors in preclinical adult-type ovarian granulosa cell tumor models
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) improve outcomes in metastatic, hormone receptor-positive breast cancer and low-grade serous ovarian carcinoma. Adult granulosa cell tumors (AGCTs) are similarly hormonally active tumors. We aimed to determine whether CDK4/6i were effective in pre-clinical models of AGCTs. Pre-clinical models used in this study include the KGN cell line, in cell culture and mouse models, and multiple novel AGCT tumoroids treated with CDK4/6i, including abemaciclib. Half-maximal inhibitory concentration (IC50) was used to assess potency of drugs. Cell number was determined using CCK8 cytotoxicity assay. Mice were treated with daily gavage with control or abemaciclib. Patients with AGCTs and prior CDK4/6i treatment were identified retrospectively. CDK4/6i demonstrated high potency in KGN cells with an IC50 value of 50 nM for abemaciclib. Adding fulvestrant to abemaciclib did not significantly affect cell proliferation. Abemaciclib demonstrated proliferation inhibition in seven AGCT tumoroids. The xenograft model demonstrated significant differences in tumor volume (p = 0.003) and tumor mass (p = 0.0002) after treatment with abemaciclib or vehicle control. Eleven patients with AGCT who received CDK4/6i treatment were identified. Best responses included partial response (3, 27.3 %), stable disease (6, 54.5 %), and progressive disease (2, 18.2 %). The median duration of response was 6 months. The regimen was well tolerated. CDK4/6i demonstrated potent inhibition of tumor cell proliferation in multiple preclinical models. CDK4/6i demonstrated tolerability and effectiveness in a small cohort of patients with AGCT. This data supports the design of clinical trials to test the efficacy of CDK4/6i in the treatment of recurrent AGCT.
Journal
Gynecologic OncologyAuthors
Funding
Cancer Center Support GrantTraining of Academic Gynecologic Oncologists01 Sequencing and Microarray FacilityTraining of Academic Gynecologic OncologistsMinistry of Education, Culture, Sports, Science and Technology FundingCancer Prevention and Research Institute of Texas FundingNational Institutes of Health FundingRIKEN Funding