title: Novel computational method for predicting polytherapy switching strategies to overcome tumor heterogeneity and evolution.
abstract: The success of targeted cancer therapy is limited by drug resistance that can result from tumor genetic heterogeneity. The current approach to address resistance typically involves initiating a new treatment after clinical/radiographic disease progression, ultimately resulting in futility in most patients. Towards a potential alternative solution, we developed a novel computational framework that uses human cancer profiling data to systematically identify dynamic, pre-emptive, and sometimes non-intuitive treatment strategies that can better control tumors in real-time. By studying lung adenocarcinoma clinical specimens and preclinical models, our computational analyses revealed that the best anti-cancer strategies addressed existing resistant subpopulations as they emerged dynamically during treatment. In some cases, the best computed treatment strategy used unconventional therapy switching while the bulk tumor was responding, a prediction we confirmed in vitro. The new framework presented here could guide the principled implementation of dynamic molecular monitoring and treatment strategies to improve cancer control.
authors.affiliation: Department of Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Vanessa D
authors.initials: VD
authors.lastname: Jonsson
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Collin M
authors.initials: CM
authors.lastname: Blakely
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Luping
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Department of Computing and Mathematical Sciences, California Institute of Technology, Pasadena, CA, USA.
authors.forename: Nikolai
authors.initials: N
authors.lastname: Matni
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Olivas
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Pazarentzos
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Gubens
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.|Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan, Kettering Cancer Center, New York, NY, USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.affiliation: Department of Control and Dynamical Systems, California Institute of Technology, Pasadena, CA, USA.|Department of Electrical Engineering, California Institute of Technology, Pasadena, CA, USA.|Department of Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Doyle
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.|Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003198:Computer Simulation; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008954:Models, Biological