Background: Adenoid Cystic Carcinoma (ACC) is a rare cancer of secretory glands, most typically occurring in the salivary glands. No approved standard of care exists for systemic therapy. To identify potentially useful therapies, we screened Food and Drug Administration (FDA)-approved and investigational therapies using a well characterized panel of low passage ACC PDX models. Based on these results, combination treatments were evaluated for additive or super-additive effects. In line with the clinical chemo resistance observed in ACC patients, we previously reported that ACC tumor models are insensitive to platinum therapies. Interestingly, histone deacetylase (HDAC) inhibitors have been shown to sensitize cancer cells to anti-cancer agents in vitro. Entinostat is an oral class 1 selective HDAC inhibitor in Phase 3 testing for ER+ breast cancer in combination with hormone therapy. To better understand the potential effects of entinostat in ACC, we evaluated this agent alone and in combination with cisplatin in ACC PDX tumor models.
Methods: Low passage ACC models were established in immune-deficient mice from primary or metastatic patient tissue and confirmed by histologic comparative analysis. Drug sensitivity studies evaluating entinostat, cisplatin and the combination were performed in three models, including ACCx5M1, ACCx6 and ACCx9. Study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion.
Results: Entinostat, cisplatin and the combination were all well tolerated with minimum cycle-based weight loss. Cisplatin tested alone (3 mg/kg weekly) was similar to control in all models, while single agent entinostat (5 mg/kg daily) showed significant anti-tumor activity in the ACCx5M1 (p<0.05) and ACCx9 (p<0.0001) models. Combination of entinostat and cisplatin exerted significant anti-tumor activity versus control in ACCx5M1 (p<0.01) and in ACCx9 versus control (p<0.0001) or entinostat alone (p<0.05). Sequence based and other characterization analysis is currently underway to correlate sensitivity and resistance between models.
Conclusion: Our studies identify entinostat as an agent of potential benefit in treating ACC and demonstrate that entinostat can induce low-dose cisplatin activity in the ACCx9 model, which harbors a mutation in the NOTCH1 gene that has been linked with chemo resistance and worse prognosis. Genomic and other characterization methods are currently underway to correlate sensitivity and resistance between models.
Citation Format: Amanda Mangold, Melissa Rundle, Nicole Spardy Burr, Alyssa Moriarty, Priscila Goncalves, Rogerio Castilho, Peter Ordentlich, Jeffrey Kaufman, Kyriakos Papadopoulos, Michael J. Wick. Activity of entinostat alone and in combination with cisplatin in a panel of low passage adenoid cystic carcinoma patient-derived xenograft (PDX) models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2146.