title: Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors.
abstract: Experimental studies have shown that one key factor in driving the emergence of drug resistance in solid tumors is tumor hypoxia, which leads to the formation of localized environmental niches where drug-resistant cell populations can evolve and survive. Hypoxia-activated prodrugs (HAPs) are compounds designed to penetrate to hypoxic regions of a tumor and release cytotoxic or cytostatic agents; several of these HAPs are currently in clinical trial. However, preliminary results have not shown a survival benefit in several of these trials. We hypothesize that the efficacy of treatments involving these prodrugs depends heavily on identifying the correct treatment schedule, and that mathematical modeling can be used to help design potential therapeutic strategies combining HAPs with standard therapies to achieve long-term tumor control or eradication. We develop this framework in the specific context of EGFR-driven non-small cell lung cancer, which is commonly treated with the tyrosine kinase inhibitor erlotinib. We develop a stochastic mathematical model, parametrized using clinical and experimental data, to explore a spectrum of treatment regimens combining a HAP, evofosfamide, with erlotinib. We design combination toxicity constraint models and optimize treatment strategies over the space of tolerated schedules to identify specific combination schedules that lead to optimal tumor control. We find that (i) combining these therapies delays resistance longer than any monotherapy schedule with either evofosfamide or erlotinib alone, (ii) sequentially alternating single doses of each drug leads to minimal tumor burden and maximal reduction in probability of developing resistance, and (iii) strategies minimizing the length of time after an evofosfamide dose and before erlotinib confer further benefits in reduction of tumor burden. These results provide insights into how hypoxia-activated prodrugs may be used to enhance therapeutic effectiveness in the clinic.
authors: School of Mathematics, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Danika
authors: D
authors: Lindsay
authors: Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Colleen M
authors: CM
authors: Garvey
authors: Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, California, United States of America.
authors: Shannon M
authors: SM
authors: Mumenthaler
authors: School of Mathematics, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors: Jasmine
authors: J
authors: Foo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019295:Computational Biology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy*; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D000069347:Erlotinib Hydrochloride