Cell signaling model connects vorinostat pharmacokinetics and tumor growth response in multiple myeloma xenografts

Multiple myeloma is a fatal hematological malignancy with high rates of drug resistance and relapse. Vorinostat, a histone deacetylase inhibitor, has shown promise in enhancing efficacy when combined with current myeloma therapies. In this study, temporal changes of critical proteins and cell proliferation were measured in myeloma cells exposed to vorinostat. A model linking biomarker dynamics to cell proliferation was developed that captured vorinostat effects on signal transduction and cell viability. The model structure and parameters were fixed to describe tumor dynamics in vivo, and tumor-specific growth and death rate parameters were estimated. The signaling model captured tumor growth inhibition in murine xenografts for a range of dose levels and regimens. This model may be used as a mechanistic bridge to link vorinostat exposure to molecular events and pharmacodynamic (PD) outcomes. It may also provide a translational platform to explore vorinostat activity as a single agent and in combination regimens.