Research article

Role of hypoxia-activated prodrugs in combination with radiation therapy: An in silico approach

  • Received: 02 April 2019 Accepted: 27 June 2019 Published: 04 July 2019
  • Tumour hypoxia has been associated with increased resistance to various cancer treatments, particularly radiation therapy. Conversely, tumour hypoxia is a validated and ideal target for guided cancer drug delivery. For this reason, hypoxia-activated prodrugs (HAPs) have been developed, which remain inactive in the body until in the presence of tissue hypoxia, allowing for an activation tendency in hypoxic regions. We present here an experimentally motivated mathematical model predicting the effectiveness of HAPs in a variety of clinical settings. We first examined HAP effectiveness as a function of the amount of tumour hypoxia and showed that the drugs have a larger impact on tumours with high levels of hypoxia. We then combined HAP treatment with radiation to examine the effects of combination therapies. Our results showed radiation-HAP combination therapies to be more effective against highly hypoxic tumours. The analysis of combination therapies was extended to consider schedule sequencing of the combination treatments. These results suggested that administering HAPs before radiation was most effective in reducing total cell number. Finally, a sensitivity analysis of the drug-related parameters was done to examine the effect of drug diffusivity and enzyme abundance on the overall effectiveness of the drug. Altogether, the results highlight the importance of the knowledge of tumour hypoxia levels before administration of HAPs in order to ensure positive results.

    Citation: Cameron Meaney, Gibin G Powathil, Ala Yaromina, Ludwig J Dubois, Philippe Lambin, Mohammad Kohandel. Role of hypoxia-activated prodrugs in combination with radiation therapy: An in silico approach[J]. Mathematical Biosciences and Engineering, 2019, 16(6): 6257-6273. doi: 10.3934/mbe.2019312

    Related Papers:

  • Tumour hypoxia has been associated with increased resistance to various cancer treatments, particularly radiation therapy. Conversely, tumour hypoxia is a validated and ideal target for guided cancer drug delivery. For this reason, hypoxia-activated prodrugs (HAPs) have been developed, which remain inactive in the body until in the presence of tissue hypoxia, allowing for an activation tendency in hypoxic regions. We present here an experimentally motivated mathematical model predicting the effectiveness of HAPs in a variety of clinical settings. We first examined HAP effectiveness as a function of the amount of tumour hypoxia and showed that the drugs have a larger impact on tumours with high levels of hypoxia. We then combined HAP treatment with radiation to examine the effects of combination therapies. Our results showed radiation-HAP combination therapies to be more effective against highly hypoxic tumours. The analysis of combination therapies was extended to consider schedule sequencing of the combination treatments. These results suggested that administering HAPs before radiation was most effective in reducing total cell number. Finally, a sensitivity analysis of the drug-related parameters was done to examine the effect of drug diffusivity and enzyme abundance on the overall effectiveness of the drug. Altogether, the results highlight the importance of the knowledge of tumour hypoxia levels before administration of HAPs in order to ensure positive results.


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    [1] R. K. Carmeliet and P. Jain, Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases, Nat. Rev. Drug Discovery , 10 (2011), 417–427.
    [2] M. R. Horsman, L. S. Mortensen, M. Busk, et al., Imaging hypoxia to improve radiotherapy outcome, Nat. Rev. Clin. Oncol, 9 (2012), 674–687.
    [3] A. Vaupel and P. Mayer, Hypoxia in cancer: Significance and impact on clinical outcome, Cancer Metastasis Rev., 26 (2007), 225–239.
    [4] P. Hockel and M. Vaupel, Tumor Hypoxia: Definitions and Current Clinical, Biologic, and Molecular Aspects, JNCI, J. Natl. Cancer Inst., 93 (2001), 266–276.
    [5] K. R. Luoto, R. Kumareswaran and R. G. Bristow, Tumor hypoxia as a driving force in genetic instability, Genome Integr., 4 (2013), 5.
    [6] L. Harrison, Hypoxia and Anemia: Factors in Decreased Sensitivity to Radiation Therapy and Chemotherapy? Oncologist , 9 (2004), 31–40.
    [7] I. F. Minchinton and A. I. Tannock, Drug Penetration in Solid Tumours, Nat. Rev. Cancer, 6 (2006), 583–592.
    [8] I. N. Mistry, M. Thomas, E. D. D. Calder, et al., Clinical Advances of Hypoxia-Activated Prodrugs in Combination With Radiation Therapy, Int. J. Radiat. Oncol. Biol. Phys., 98 (2017), 1183–1196.
    [9] F. W. Hunter, B. G. Wouters and W. R. Wilson, Hypoxia-activated prodrugs: Paths forward in the era of personalised medicine, Br. J. Cancer, 114 (2016), 1071–1077.
    [10] J. D. Sun, Q. Liu, J. Wang, et al., TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: Optimization of dosing regimens and schedules, Cancer Chemother. Pharmacol., 69 (2012), 1487–1498.
    [11] S. G. Peeters, C. M. Zegers, R. Biemans, et al., TH-302 in Combination with Radiotherapy Enhances the Therapeutic Outcome and Is Associated with Pretreatment [18 F]HX4 Hypoxia PET Imaging, Clin. Cancer Res., 21 (2015), 2984–2992.
    [12] A. Yaromina, M. Granzier, R. Biemans, et al., A novel concept for tumour targeting with radiation: Inverse dose-painting or targeting the Low Drug Uptake Volume, Radiother. Oncology, 124 (2017), 513–520.
    [13] R. M. Phillips, Targeting the hypoxic fraction of tumours using hypoxiaactivated prodrugs, Cancer Chemother. Pharmacol., 77 (2016), 441–457.
    [14] M. Kohandel, M. Kardar, M. Milosevic, et al., Dynamics of tumor growth and combination of anti-angiogenic and cytotoxic therapies, Phys. Med. Biol., 52 (2007), 3665–3677.
    [15] S. F. Petit, A. L. Dekker, R. Seigneuric, et al., Intra-voxel heterogeneity influences the dose prescription for dose-painting with radiotherapy: A modelling study, Phys. Med. Biol., 54 (2009), 2179–2196.
    [16] G. Powathil, M. Kohandel, M. Milosevic, et al., Modeling the spatial distribution of chronic tumor hypoxia: Implications for experimental and clinical studies, Comput. Math. Methods Med., 2012 (2012), 410602.
    [17] S. Yonucu, Y. Defne, C. Phipps, et al., Quantifying the effects of antiangiogenic and chemotherapy drug combinations on drug delivery and treatment efficacy, PLoS Comput. Biol., 13 (2017), e1005724.
    [18] A. Foehrenbacher, K. Patel, M. R. Abbattista, et al., The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104, Front. Oncology, 3 (2013), 1–18.
    [19] A. Foehrenbacher, T. W. Secomb, W. R. Wilson, et al., Design of Optimized Hypoxia-Activated Prodrugs Using Pharmacokinetic/Pharmacodynamic Modeling, Front. Oncology, 3 (2013), 33–35.
    [20] K. O. Hicks, F. B. Pruijn, T. W. Secomb, et al., Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs, J. Nat. Cancer Inst., 98 (2006), 1118–1128.
    [21] D. Lindsay, C. M. Garvey, S. M. Mumenthaler, et al., Leveraging Hypoxia-Activated Prodrugs to Prevent Drug Resistance in Solid Tumors, PLoS Comp. Biol., 12 (2016), 1–25.
    [22] T. W. Secomb, R. Hsu, R. D. Braun, et al., Theoretical simulation of oxygen transport to tumors by three-dimensional networks of microvessels, Oxygen Transp. Tissue XX, 454 (1998), 629–634. 1998.
    [23] R. Weinberg, The Biology of Cancer, United States: Garland Science, 2006.
    [24] C. Hajj, J. Russell, C. P. Hart, et al., A combination of radiation and the hypoxia-activated prodrug evofosfamide (TH-302) is efficacious against a human orthotopic pancreatic tumor model, Trans. Oncology, 10 (2017), 760–765.
    [25] J. K. Saggar and I. F. Tannock, Activity of the hypoxia-activated pro-drug TH-302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy, Int. J. Cancer, 134 (2014), 2726–2734.
    [26] G. J. Weiss, J. R. Infante, E. G. Chiorean, et al., Phase 1 study of the safety, tolerability, and pharmacokinetics of TH-302, a hypoxia-activated prodrug, in patients with advanced solid malignancies, Clin. Cancer Res., 17 (2011), 2997–3004.
    [27] W. R. Wilson and M. P. Hay, Targeting hypoxia in cancer therapy, Nat. Rev. Cancer, 11 (2011), 393–410.
    [28] G. D. Smith, Numerical solution of partial differential equations: Finite difference methods. Oxford: Oxford university press, 1985.
    [29] K. J. Nytko, I. Grgic, S. Bender, et al., The hypoxia-activated prodrug evofosfamide in combination with multiple regimens of radiotherapy, Oncotarget, 8 (2017), 23702–23712.
    [30] C. V. M. Verhagen, D. M. Vossen, K. Borgmann, et al., Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects in vitro and poor outcome in patients with advanced head and neck squamous cell carcinoma, Oncotarget, 9 (2018), 18198–18213.
    [31] J. Stingele, R. Bellelli and S. J. Boulton, Mechanisms of DNA-protein crosslink repair, Nat. Rev. Mol. Cell Biol., 18 (2017), 563–573.
    [32] S. M. Jamieson, P. Tsai, M. K. Kondratyev, et al., Evofosfamide for the treatment of human papillomavirus-negative head and neck squamous cell carcinoma., JCI Insight, 3 (2018), e122204.
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