title: Logic-Based and Cellular Pharmacodynamic Modeling of Bortezomib Responses in U266 Human Myeloma Cells.
abstract: Systems models of biological networks show promise for informing drug target selection/qualification, identifying lead compounds and factors regulating disease progression, rationalizing combinatorial regimens, and explaining sources of intersubject variability and adverse drug reactions. However, most models of biological systems are qualitative and are not easily coupled with dynamical models of drug exposure-response relationships. In this proof-of-concept study, logic-based modeling of signal transduction pathways in U266 multiple myeloma (MM) cells is used to guide the development of a simple dynamical model linking bortezomib exposure to cellular outcomes. Bortezomib is a commonly used first-line agent in MM treatment; however, knowledge of the signal transduction pathways regulating bortezomib-mediated cell cytotoxicity is incomplete. A Boolean network model of 66 nodes was constructed that includes major survival and apoptotic pathways and was updated using responses to several chemical probes. Simulated responses to bortezomib were in good agreement with experimental data, and a reduction algorithm was used to identify key signaling proteins. Bortezomib-mediated apoptosis was not associated with suppression of nuclear factor κB (NFκB) protein inhibition in this cell line, which contradicts a major hypothesis of bortezomib pharmacodynamics. A pharmacodynamic model was developed that included three critical proteins (phospho-NFκB, BclxL, and cleaved poly (ADP ribose) polymerase). Model-fitted protein dynamics and cell proliferation profiles agreed with experimental data, and the model-predicted IC50 (3.5 nM) is comparable to the experimental value (1.5 nM). The cell-based pharmacodynamic model successfully links bortezomib exposure to MM cellular proliferation via protein dynamics, and this model may show utility in exploring bortezomib-based combination regimens.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York (V.L.C., M.A.O., D.E.M.); and Office of Clinical Pharmacology, Food and Drug Administration, Silver Springs, Maryland (D.R.A.).
authors.forename: Vaishali L
authors.initials: VL
authors.lastname: Chudasama
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York (V.L.C., M.A.O., D.E.M.); and Office of Clinical Pharmacology, Food and Drug Administration, Silver Springs, Maryland (D.R.A.).
authors.forename: Meric A
authors.initials: MA
authors.lastname: Ovacik
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York (V.L.C., M.A.O., D.E.M.); and Office of Clinical Pharmacology, Food and Drug Administration, Silver Springs, Maryland (D.R.A.).
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Abernethy
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York (V.L.C., M.A.O., D.E.M.); and Office of Clinical Pharmacology, Food and Drug Administration, Silver Springs, Maryland (D.R.A.) dmager@buffalo.edu.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008128:Logic; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D051020:bcl-X Protein; D000069286:Bortezomib; D011065:Poly(ADP-ribose) Polymerases