Cell Signaling Model Connects Vorinostat Pharmacokinetics and Tumor Growth Response in Multiple Myeloma Xenografts

Abstract

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.

Figure 1

Schematic of signaling model linking vorinostat exposure‐response relationships in multiple myeloma cells and xenografts. “Vort Conc” represents vorinostat pharmacokinetics (PK), which was a bi‐exponential in vitro degradation profile or a two‐compartment in vivo PK model. “Cells” denotes the final pharmacodynamic response (U266 in vitro cell proliferation or in vivo tumor volume). The shaded green compartments for p21, cleaved poly ADP‐ribose polymerase (PARP), Bcl‐xL, p nuclear factor‐kappa β (NF‐κβ), and p53 represent the measured relative expressions of these proteins, whereas the blue compartments represent empirical transit compartments. Stimulation is denoted by and inhibition is denoted by .

Figure 2

Representative immunoblotting time course of vorinostat effects on cleaved poly ADP‐ribose polymerase (PARP) (a) and Bcl‐xL (b) n U266 cells at 5 and 2 μM.

Figure 3

Time course of p21 (a), cleaved poly ADP‐ribose polymerase (PARP) (b), Bcl‐xL (c), pNF‐κB (d), p53 (e), and U266 cell proliferation (f) under vorinostat exposure (2 or 5 μM). Symbols represent experimentally measured data points, error bars represent SD (n = 3), and lines represent model‐fitted profiles (red = control; blue = vorinostat 2 μM; and green = vorinostat 5 μM).

Figure 4

Simulated protein dynamics for p21 (a), cleaved poly ADP‐ribose polymerase (PARP) (b), Bcl‐xL (c), and tumor growth inhibition profiles (d) for four different vorinostat dosing regimens in LAGκ‐1B xenografts. Symbols represent data digitized from an original publication,24 and lines represent model simulated (protein biomarkers) or fitted (tumor volume) profiles (black = control; red = 60 mg/kg q.d. × 5 day dosing; green = 100 mg/kg q.d. × 5 day dosing; blue = 100 mg/kg q.d. × 2 day dosing; and pink = 300 mg/kg q.d. × 2 day dosing).