| Autor: |
Ananthapadmanabhan V; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA., Frost TC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA., Soroko KM; Experimental Therapeutics Core at Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Knott A; Experimental Therapeutics Core at Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Magliozzi BJ; Experimental Therapeutics Core at Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Gokhale PC; Experimental Therapeutics Core at Dana-Farber Cancer Institute, Boston, Massachusetts, USA., Tirunagaru VG; Rain Therapeutics, Newark, California, USA., Doebele RC; Rain Therapeutics, Newark, California, USA., DeCaprio JA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA. |
| Abstrakt: |
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 (TP53). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53. MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies. |
