Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs
Abstract Hypoxia, a low level of oxygen in the tissue, arises due to an imbalance between the vascular oxygen supply and oxygen demand by the surrounding cells. Typically, hypoxia is viewed as a negative marker of patients’ survival, because of its implication in the development of aggressive tumors...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | npj Systems Biology and Applications |
| Online Access: | https://doi.org/10.1038/s41540-023-00327-z |
| _version_ | 1827388394496327680 |
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| author | Shreya Mathur Shannon Chen Katarzyna A. Rejniak |
| author_facet | Shreya Mathur Shannon Chen Katarzyna A. Rejniak |
| author_sort | Shreya Mathur |
| collection | DOAJ |
| description | Abstract Hypoxia, a low level of oxygen in the tissue, arises due to an imbalance between the vascular oxygen supply and oxygen demand by the surrounding cells. Typically, hypoxia is viewed as a negative marker of patients’ survival, because of its implication in the development of aggressive tumors and tumor resistance. Several drugs that specifically target the hypoxic cells have been developed, providing an opportunity for exploiting hypoxia to improve cancer treatment. Here, we consider combinations of hypoxia-activated pro-drugs (HAPs) and two compounds that transiently increase intratumoral hypoxia: a vasodilator and a metabolic sensitizer. To effectively design treatment protocols with multiple compounds we used mathematical micro-pharmacology modeling and determined treatment schedules that take advantage of heterogeneous and dynamically changing oxygenation in tumor tissue. Our model was based on data from murine pancreatic cancers treated with evofosfamide (as a HAP) and either hydralazine (as a vasodilator), or pyruvate (as a metabolic sensitizer). Subsequently, this model was used to identify optimal schedules for different treatment combinations. Our simulations showed that schedules of HAPs with the vasodilator had a bimodal distribution, while HAPs with the sensitizer showed an elongated plateau. All schedules were more successful than HAP monotherapy. The three-compound combination had three local optima, depending on the HAPs clearance from the tissue interstitium, each two-fold more effective than baseline HAP treatment. Our study indicates that the three-compound therapy administered in the defined order will improve cancer response and that designing complex schedules could benefit from the use of mathematical modeling. |
| first_indexed | 2024-03-08T16:17:10Z |
| format | Article |
| id | doaj.art-36b9425eec924a02b2b1bf9e78e2bbf5 |
| institution | Directory Open Access Journal |
| issn | 2056-7189 |
| language | English |
| last_indexed | 2024-03-08T16:17:10Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Systems Biology and Applications |
| spelling | doaj.art-36b9425eec924a02b2b1bf9e78e2bbf52024-01-07T12:31:43ZengNature Portfolionpj Systems Biology and Applications2056-71892024-01-0110111410.1038/s41540-023-00327-zExploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugsShreya Mathur0Shannon Chen1Katarzyna A. Rejniak2H. Lee Moffitt Cancer Center and Research Institute, IMO High School Internship ProgramH. Lee Moffitt Cancer Center and Research Institute, IMO High School Internship ProgramH. Lee Moffitt Cancer Center and Research Institute, Integrated Mathematical Oncology DepartmentAbstract Hypoxia, a low level of oxygen in the tissue, arises due to an imbalance between the vascular oxygen supply and oxygen demand by the surrounding cells. Typically, hypoxia is viewed as a negative marker of patients’ survival, because of its implication in the development of aggressive tumors and tumor resistance. Several drugs that specifically target the hypoxic cells have been developed, providing an opportunity for exploiting hypoxia to improve cancer treatment. Here, we consider combinations of hypoxia-activated pro-drugs (HAPs) and two compounds that transiently increase intratumoral hypoxia: a vasodilator and a metabolic sensitizer. To effectively design treatment protocols with multiple compounds we used mathematical micro-pharmacology modeling and determined treatment schedules that take advantage of heterogeneous and dynamically changing oxygenation in tumor tissue. Our model was based on data from murine pancreatic cancers treated with evofosfamide (as a HAP) and either hydralazine (as a vasodilator), or pyruvate (as a metabolic sensitizer). Subsequently, this model was used to identify optimal schedules for different treatment combinations. Our simulations showed that schedules of HAPs with the vasodilator had a bimodal distribution, while HAPs with the sensitizer showed an elongated plateau. All schedules were more successful than HAP monotherapy. The three-compound combination had three local optima, depending on the HAPs clearance from the tissue interstitium, each two-fold more effective than baseline HAP treatment. Our study indicates that the three-compound therapy administered in the defined order will improve cancer response and that designing complex schedules could benefit from the use of mathematical modeling.https://doi.org/10.1038/s41540-023-00327-z |
| spellingShingle | Shreya Mathur Shannon Chen Katarzyna A. Rejniak Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs npj Systems Biology and Applications |
| title | Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs |
| title_full | Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs |
| title_fullStr | Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs |
| title_full_unstemmed | Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs |
| title_short | Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs |
| title_sort | exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia activated pro drugs |
| url | https://doi.org/10.1038/s41540-023-00327-z |
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