title: Combinatorial chemotherapeutic efficacy in non-Hodgkin lymphoma can be predicted by a signaling model of CD20 pharmacodynamics.
abstract: Combination chemotherapy represents the standard-of-care for non-Hodgkin lymphoma. However, the development of new therapeutic regimens is empirical and this approach cannot be used prospectively to identify novel or optimal drug combinations. Quantitative system pharmacodynamic models could promote the discovery and development of combination regimens based upon first principles. In this study, we developed a mathematical model that integrates temporal patterns of drug exposure, receptor occupancy, and signal transduction to predict the effects of the CD20 agonist rituximab in combination with rhApo2L/TNF-related apoptosis inducing ligand or fenretinide, a cytotoxic retinoid, upon growth kinetics in non-Hodgkin lymphoma xenografts. The model recapitulated major regulatory mechanisms, including target-mediated disposition of rituximab, modulation of proapoptotic intracellular signaling induced by CD20 occupancy, and the relative efficacy of death receptor isoforms. The multiscale model coupled tumor responses to individual anticancer agents with their mechanisms of action in vivo, and the changes in Bcl-xL and Fas induced by CD20 occupancy were linked to explain the synergy of these drugs. Tumor growth profiles predicted by the model agreed with cell and xenograft data, capturing the apparent pharmacologic synergy of these agents with fidelity. Together, our findings provide a mechanism-based platform for exploring new regimens with CD20 agonists.
authors.affiliation: Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14260, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Harrold
authors.forename: Robert M
authors.initials: RM
authors.lastname: Straubinger
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D018951:Antigens, CD20 / Q000032:analysis / Q000502:physiology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D017313:Fenretinide / Q000008:administration & dosage / Q000493:pharmacokinetics; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D051379:Mice; D008954:Models, Biological; D000069283:Rituximab; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D053221:TNF-Related Apoptosis-Inducing Ligand; D017313:Fenretinide; D000069283:Rituximab