Approaches to combat hypoxia in cancer therapy and the potential for in silico models in their evaluation

Forster, Jake C.; Marcu, Loredana G.; Bezak, Eva

doi:10.1016/j.ejmp.2019.07.006

Cited by 18 publications

(16 citation statements)

References 130 publications

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“…In addition to this method, hypoxia has earlier also been accounted for in treatment planning studies applying dose and/or LET painting, i.e. where the hypoxic volumes receive either increased dose and/or increased LET values, respectively [43][44][45]. Malinen and Søvik [43] found that hypoxia dose painting appeared to be especially attractive for protons, while both LET and dose painting has the potential to increase the tumor control probability for heavier ions like lithium and carbon.…”

Section: Discussionmentioning

confidence: 99%

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors

et al. 2020

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The increased radioresistance of hypoxic cells compared to well-oxygenated cells is quantified by the oxygen enhancement ratio (OER). In this study we created a FLUKA Monte Carlo based tool for inclusion of both OER and relative biological effectiveness (RBE) in biologically weighted dose (ROWD) calculations in proton therapy and applied this to explore the impact of hypoxia. Methods: The RBE-weighted dose was adapted for hypoxia by making RBE model parameters dependent on the OER, in addition to the linear energy transfer (LET). The OER depends on the partial oxygen pressure (pO 2 ) and LET. To demonstrate model performance, calculations were done with spread-out Bragg peaks (SOBP) in water phantoms with pO 2 ranging from strongly hypoxic to normoxic (0.01-30 mmHg) and with a head and neck cancer proton plan optimized with an RBE of 1.1 and pO 2 estimated voxel-by-voxel using [ 18 F]-EF5 PET. An RBE of 1.1 and the Rørvik RBE model were used for the ROWD calculations. Results: The SOBP in water had decreasing ROWD with decreasing pO 2 . In the plans accounting for oxygenation, the median target doses were approximately a factor 1.1 lower than the corresponding plans which did not consider the OER. Hypoxia adapted target ROWDs were considerably more heterogeneous than the RBE 1.1weighted doses. Conclusion:We realized a Monte Carlo based tool for calculating the ROWD. Read-in of patient pO 2 and estimation of ROWD with flexibility in choice of RBE model was achieved, giving a tool that may be useful in future clinical applications of hypoxia-guided particle therapy.

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Section: Discussionmentioning

confidence: 99%

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors

et al. 2020

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“…In this study, HV was significantly decreased in Inter-FRT 18 F-FMISO PET/CT at 21 Gy; meanwhile, PTV reduction in the early phase of treatment was markedly less pronounced than that of HV. It is well-known that tumor cells with hypoxia are more radiation-resistant than oxygenated counterparts ( 24 , 25 ). Thus, hypoxic cancer cells are not likely killed earlier by irradiation compared with non-hypoxic ones.…”

Section: Discussionmentioning

confidence: 99%

Dual-Tracer Assessment of Dynamic Changes in Reoxygenation and Proliferation Decrease During Fractionated Radiotherapy in Murine Tumors

Zhang

et al. 2020

Front. Oncol.

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Objective: The present work aimed to assess reoxygenation and tumor inhibition during fractionated radiotherapy (FRT) in murine tumors using 18 F-fluoromisonidazole ( 18 F-FMISO) and 18 F-fluorothymidine ( 18 F-FLT) based micro positron emission tomography/computed tomography (PET/CT). Materials and Methods: A nude mouse xenograft model was established with the head and neck squamous carcinoma cell (FaDu), followed by administration of FRT. Imaging was carried out with both 18 F-FMISO and 18 F-FLT PET/CT, prior to FRT (Pre-FRT, 0 Gy), during FRT (Inter-FRT, 21 Gy), and after FRT (Post-FRT, 40 Gy). The maximum standardized uptake (SUVmax) and tumor-to-normal muscle ratio (TNR) were determined in regions of interest (ROIs) in 18 F-FMISO and 18 F-FLT PET/CT images. Then, hypoxic (HV) and proliferative tumor (PTV) volumes obtained by PET/CT were analyzed. Immunohistochemistry was performed to analyze the changes of hypoxia-inducible factor- (HIF)-1α, carbonic anhydrase 9 (CAIX), Ki67 and proliferating cell nuclear antigen (PCNA). Associations of the levels of these biomarkers with PET/CT parameters were analyzed. Results: 18 F-FMISO PET/CT demonstrated markedly elevated reduction rates of SUVmax (30.3 vs. 14.5%, p = 0.012), TNR (27.9 vs. 18.3%, p = 0.032) and HV (85.0 vs. 71.4%, p = 0.047) from Pre-FRT to Inter-FRT compared with values from Inter-FRT to Post-FRT. Meanwhile, PTV reduction rate in 18 F-FLT PET/CT from Pre-FRT to Inter-FRT was significantly decreased compared with that from Inter-FRT to Post-FRT (21.2 vs. 82.7%, p = 0.012). Tumor HIF-1α, CAIX, Ki67, and PCNA amounts were continuously down-regulated during radiotherapy. TNR (FMISO) showed significant correlations with HIF-1α ( r = 0.692, p = 0.015) and CAIX ( r = 0.801, p = 0.006) amounts in xenografts, while associations of SUVmax (FMISO) with hypoxia markers were weak ( r = 0.418, p = 0.041 and r = 0.389, p = 0.037, respectively). SUVmax (FLT) was significantly correlated with Ki67 ( r = 0.792, p = 0.003) and PCNA ( r = 0.837, p = 0.004). Conclusions: Tumor reoxygenation occurs early during radiotherapy, while inhibition of cell proliferation by tumoricidal effects mainly takes place gradually with the course of radiotherapy. 18 F-FMISO and 18 F-FLT PET/CT are sensitive and non-invasive tools for the monitoring of tumor reoxygenation and pro...

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“…Radiotherapy is another cancer treatment option that uses radiation to inhibit cancer progression and induce cell death [ 274 ]. However, due to specific conditions in the TME such as hypoxia, cancer cells could develop resistance to radiotherapy, and the factors involved in this phenomenon should be elucidated [ 275 , 276 ].…”

Section: Exosomes and Cancer Resistancementioning

confidence: 99%

Emerging role of exosomes in cancer progression and tumor microenvironment remodeling

et al. 2022

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Cancer is one of the leading causes of death worldwide, and the factors responsible for its progression need to be elucidated. Exosomes are structures with an average size of 100 nm that can transport proteins, lipids, and nucleic acids. This review focuses on the role of exosomes in cancer progression and therapy. We discuss how exosomes are able to modulate components of the tumor microenvironment and influence proliferation and migration rates of cancer cells. We also highlight that, depending on their cargo, exosomes can suppress or promote tumor cell progression and can enhance or reduce cancer cell response to radio- and chemo-therapies. In addition, we describe how exosomes can trigger chronic inflammation and lead to immune evasion and tumor progression by focusing on their ability to transfer non-coding RNAs between cells and modulate other molecular signaling pathways such as PTEN and PI3K/Akt in cancer. Subsequently, we discuss the use of exosomes as carriers of anti-tumor agents and genetic tools to control cancer progression. We then discuss the role of tumor-derived exosomes in carcinogenesis. Finally, we devote a section to the study of exosomes as diagnostic and prognostic tools in clinical courses that is important for the treatment of cancer patients. This review provides a comprehensive understanding of the role of exosomes in cancer therapy, focusing on their therapeutic value in cancer progression and remodeling of the tumor microenvironment. Graphical Abstract

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Approaches to combat hypoxia in cancer therapy and the potential for in silico models in their evaluation

Cited by 18 publications

References 130 publications

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors

The FLUKA Monte Carlo code coupled with an OER model for biologically weighted dose calculations in proton therapy of hypoxic tumors

Dual-Tracer Assessment of Dynamic Changes in Reoxygenation and Proliferation Decrease During Fractionated Radiotherapy in Murine Tumors

Emerging role of exosomes in cancer progression and tumor microenvironment remodeling

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