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Advances in Experimental Radiotherapy

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 50580

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Special Issue Editors

Prof. Dr. Rob P. Coppes

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Guest Editor

1. Section Molecular Cell Biology, Department of Biomedical Sciences of Cells & Systems, FB30, University Medical Center Groningen, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands
2. Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, P.O. Box 196, 9700 AD Groningen, The Netherlands
Interests: radiation biology; normal tissue effects; stem cells; organoids; predictive modeling; stemness signaling

Prof. Dr. Marc A.G.G. Vooijs

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Guest Editor

Department of Radiotherapy (MAASTRO)/GROW, School for Developmental Biology and Oncology, Maastricht University, The Netherlands
Interests: tumor microenvironment and treatment resistance; hypoxia; HIF; Notch signaling; cancer stem cells
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Special Issue Information

Dear Colleagues,

Radiotherapy remains one of the most common and rapidly evolving treatments for cancer. However, currently, radiotherapy is rarely given as a single treatment but increasingly in combination with biologicals and taking into account biological mechanisms. More accurate therapies such as proton and carbon therapy have opened novel avenues for alternative dose planning/distribution, but biological and mechanistic differences in the cellular response between photon and particle treatment need further elucidation. Combination therapies involving hyperthermia, immune checkpoint inhibitors DDR inhibitors, and (stem cell) metabolism interference are currently finding their way to the clinic. In addition to these, modulation and prediction of response to radiation involving cancer therapies will optimize current empirical data-driven models based on dose distribution and clinical outcome. (Cancer) stem cell response, circulating biomarkers, and the microbiome have large implications on the prediction and adaptation of the radiation response.

This Special Issue of Cancers on “Advances in Experimental Radiotherapy” features the current standing of the field of radiotherapy and the application and potential emerging biological approaches to improve treatment outcome in radiotherapy. For ultimate clinical application of combination treatments, we must better understand the biology of the radiation response and ways to predict and develop novel ways to modulate both tumor and normal tissue responses. Those factors will ultimately increase tumor control and quality of life of the patients.

Prof. Dr. Rob P. Coppes
Prof. Dr. Marc A.G.G. Vooijs
Guest Editors

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Keywords

radiotherapy
immunotherapy
stem cells
hyperthermia
protons
carbons
metabolism
DNA damage response
biomarkers
microbiome

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Published Papers (11 papers)

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Research

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14 pages, 2908 KiB

Open AccessArticle

Heavy Ion Minibeam Therapy: Side Effects in Normal Brain

by John G. Eley, Catherine W. Haga, Asaf Keller, Ellis M. Lazenby, Charles Raver, Adam Rusek, Farrokh Avraham Dilmanian, Sunil Krishnan and Jaylyn Waddell

Cancers 2021, 13(24), 6207; https://doi.org/10.3390/cancers13246207 - 9 Dec 2021

Cited by 5 | Viewed by 2908

Abstract

The purpose of this work was to investigate whether minibeam therapy with heavy ions might offer improvements of the therapeutic ratio for the treatment of human brain cancers. To assess neurotoxicity, we irradiated normal juvenile rats using 120 MeV lithium-7 ions at an absorbed integral dose of 20 Gy. Beams were configured either as a solid parallel circular beam or as an array of planar parallel minibeams having 300-micron width and 1-mm center-to-center spacing within a circular array. We followed animals for 6 months after treatment and utilized behavioral testing and immunohistochemical studies to investigate the resulting cognitive impairment and chronic pathologic changes. We found both solid-beam therapy and minibeam therapy to result in cognitive impairment compared with sham controls, with no apparent reduction in neurotoxicity using heavy ion minibeams instead of solid beams under the conditions of this study. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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24 pages, 3938 KiB

Open AccessArticle

Tyrosine Kinase c-MET as Therapeutic Target for Radiosensitization of Head and Neck Squamous Cell Carcinomas

by Lina Lüttich, María José Besso, Stephan Heiden, Lydia Koi, Michael Baumann, Mechthild Krause, Anna Dubrovska, Annett Linge, Ina Kurth and Claudia Peitzsch

Cancers 2021, 13(8), 1865; https://doi.org/10.3390/cancers13081865 - 14 Apr 2021

Cited by 13 | Viewed by 4382

Abstract

The receptor tyrosine kinase c-MET activates intracellular signaling and induces cell proliferation, epithelial-to-mesenchymal-transition and migration. Within the present study, we validated the prognostic value of c-MET in patients with head and neck squamous cell carcinoma (HNSCC) treated with radio(chemo)therapy using the Cancer Genome Atlas database and found an association of increased MET gene expression and protein phosphorylation with reduced disease-specific and progression-free survival. To investigate the role of c-MET-dependent radioresistance, c-MET-positive cells were purified from established HNSCC cell lines and a reduced radiosensitivity and enhanced sphere-forming potential, compared to the c-MET-depleted cell population, was found in two out of four analyzed cell lines pointing to regulatory heterogeneity. We showed that c-MET is dynamically regulated after irradiation in vitro and in vivo. Interestingly, no direct impact of c-MET on DNA damage repair was found. The therapeutic potential of eight c-MET targeting agents in combination with irradiation demonstrated variable response rates in six HNSCC cell lines. Amongst them, crizotinib, foretinib, and Pha665752 exhibited the strongest radiosensitizing effect. Kinase activity profiling showed an association of crizotinib resistance with compensatory PI3K/AKT and MAP kinase signaling. Overall, our results indicate that c-MET is conferring radioresistance in HNSCC through modulation of intracellular kinase signaling and stem-like features. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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15 pages, 9106 KiB

Open AccessArticle

Comparative Therapeutic Exploitability of Acute Adaptation Mechanisms to Photon and Proton Irradiation in 3D Head and Neck Squamous Cell Carcinoma Cell Cultures

by Annina Meerz, Sara Sofia Deville, Johannes Müller and Nils Cordes

Cancers 2021, 13(6), 1190; https://doi.org/10.3390/cancers13061190 - 10 Mar 2021

Cited by 13 | Viewed by 3058 | Correction

Abstract

For better tumor control, high-precision proton beam radiation therapy is currently being intensively discussed relative to conventional photon therapy. Here, we assumed that radiation type-specific molecular response profiles in more physiological 3D, matrix-based head and neck squamous cell carcinoma (HNSCC) cell cultures can be identified and therapeutically exploited. While proton irradiation revealed superimposable clonogenic survival and residual DNA double strand breaks (DSB) relative to photon irradiation, kinome profiles showed quantitative differences between both irradiation types. Pharmacological inhibition of a subset of radiation-induced kinases, predominantly belonging to the mitogen-activated protein kinase (MAPK) family, failed to sensitize HNSCC cells to either proton or photon irradiation. Likewise, inhibitors for ATM, DNA-PK and PARP did not discriminate between proton and photon irradiation but generally elicited a radiosensitization. Conclusively, our results suggest marginal cell line-specific differences in the radiosensitivity and DSB repair without a superiority of one radiation type over the other in 3D grown HNSCC cell cultures. Importantly, radiation-induced activity changes of cytoplasmic kinases induced during the first, acute phase of the cellular radiation response could neither be exploited for sensitization of HNSCC cells to photon nor proton irradiation. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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15 pages, 2390 KiB

Open AccessArticle

FLASH Proton Pencil Beam Scanning Irradiation Minimizes Radiation-Induced Leg Contracture and Skin Toxicity in Mice

by Shannon Cunningham, Shelby McCauley, Kanimozhi Vairamani, Joseph Speth, Swati Girdhani, Eric Abel, Ricky A. Sharma, John P. Perentesis, Susanne I. Wells, Anthony Mascia and Mathieu Sertorio

Cancers 2021, 13(5), 1012; https://doi.org/10.3390/cancers13051012 - 1 Mar 2021

Cited by 151 | Viewed by 7456

Abstract

Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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21 pages, 3294 KiB

Open AccessArticle

Neuroprotection of Radiosensitive Juvenile Mice by Ultra-High Dose Rate FLASH Irradiation

by Yasaman Alaghband, Samantha N. Cheeks, Barrett D. Allen, Pierre Montay-Gruel, Ngoc-Lien Doan, Benoit Petit, Patrik Goncalves Jorge, Erich Giedzinski, Munjal M. Acharya, Marie-Catherine Vozenin and Charles L. Limoli

Cancers 2020, 12(6), 1671; https://doi.org/10.3390/cancers12061671 - 24 Jun 2020

Cited by 93 | Viewed by 5603

Abstract

Major advances in high precision treatment delivery and imaging have greatly improved the tolerance of radiotherapy (RT); however, the selective sparing of normal tissue and the reduction of neurocognitive side effects from radiation-induced toxicities remain significant problems for pediatric patients with brain tumors. While the overall survival of pediatric patients afflicted with medulloblastoma (MB), the most common type primary brain cancer in children, remains high (≥80%), lifelong neurotoxic side-effects are commonplace and adversely impact patients’ quality of life. To circumvent these clinical complications, we have investigated the capability of ultra-high dose rate FLASH-radiotherapy (FLASH-RT) to protect the radiosensitive juvenile mouse brain from normal tissue toxicities. Compared to conventional dose rate (CONV) irradiation, FLASH-RT was found to ameliorate radiation-induced cognitive dysfunction in multiple independent behavioral paradigms, preserve developing and mature neurons, minimize microgliosis and limit the reduction of the plasmatic level of growth hormone. The protective “FLASH effect” was pronounced, especially since a similar whole brain dose of 8 Gy delivered with CONV-RT caused marked reductions in multiple indices of behavioral performance (objects in updated location, novel object recognition, fear extinction, light-dark box, social interaction), reductions in the number of immature (doublecortin⁺) and mature (NeuN⁺) neurons and increased neuroinflammation, adverse effects that were not found with FLASH-RT. Our data point to a potentially innovative treatment modality that is able to spare, if not prevent, many of the side effects associated with long-term treatment that disrupt the long-term cognitive and emotional well-being of medulloblastoma survivors. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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Review

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25 pages, 8418 KiB

Open AccessReview

Linking Serine/Glycine Metabolism to Radiotherapy Resistance

by Anaís Sánchez-Castillo, Marc Vooijs and Kim R. Kampen

Cancers 2021, 13(6), 1191; https://doi.org/10.3390/cancers13061191 - 10 Mar 2021

Cited by 31 | Viewed by 6487

Abstract

The activation of de novo serine/glycine biosynthesis in a subset of tumors has been described as a major contributor to tumor pathogenesis, poor outcome, and treatment resistance. Amplifications and mutations of de novo serine/glycine biosynthesis enzymes can trigger pathway activation; however, a large group of cancers displays serine/glycine pathway overexpression induced by oncogenic drivers and unknown regulatory mechanisms. A better understanding of the regulatory network of de novo serine/glycine biosynthesis activation in cancer might be essential to unveil opportunities to target tumor heterogeneity and therapy resistance. In the current review, we describe how the activation of de novo serine/glycine biosynthesis in cancer is linked to treatment resistance and its implications in the clinic. To our knowledge, only a few studies have identified this pathway as metabolic reprogramming of cancer cells in response to radiation therapy. We propose an important contribution of de novo serine/glycine biosynthesis pathway activation to radioresistance by being involved in cancer cell viability and proliferation, maintenance of cancer stem cells (CSCs), and redox homeostasis under hypoxia and nutrient-deprived conditions. Current approaches for inhibition of the de novo serine/glycine biosynthesis pathway provide new opportunities for therapeutic intervention, which in combination with radiotherapy might be a promising strategy for tumor control and ultimately eradication. Further research is needed to gain molecular and mechanistic insight into the activation of this pathway in response to radiation therapy and to design sophisticated stratification methods to select patients that might benefit from serine/glycine metabolism-targeted therapies in combination with radiotherapy. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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17 pages, 1164 KiB

Open AccessReview

The Radiation-Induced Regenerative Response of Adult Tissue-Specific Stem Cells: Models and Signaling Pathways

by Paola Serrano Martinez, Lorena Giuranno, Marc Vooijs and Robert P. Coppes

Cancers 2021, 13(4), 855; https://doi.org/10.3390/cancers13040855 - 18 Feb 2021

Cited by 13 | Viewed by 3344

Abstract

Radiotherapy is involved in the treatment of many cancers, but damage induced to the surrounding normal tissue is often inevitable. Evidence suggests that the maintenance of homeostasis and regeneration of the normal tissue is driven by specific adult tissue stem/progenitor cells. These tasks involve the input from several signaling pathways. Irradiation also targets these stem/progenitor cells, triggering a cellular response aimed at achieving tissue regeneration. Here we discuss the currently used in vitro and in vivo models and the involved specific tissue stem/progenitor cell signaling pathways to study the response to irradiation. The combination of the use of complex in vitro models that offer high in vivo resemblance and lineage tracing models, which address organ complexity constitute potential tools for the study of the stem/progenitor cellular response post-irradiation. The Notch, Wnt, Hippo, Hedgehog, and autophagy signaling pathways have been found as crucial for driving stem/progenitor radiation-induced tissue regeneration. We review how these signaling pathways drive the response of solid tissue-specific stem/progenitor cells to radiotherapy and the used models to address this. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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23 pages, 1197 KiB

Open AccessEditor’s ChoiceReview

Radiotherapy–Immunotherapy Combination: How Will We Bridge the Gap Between Pre-Clinical Promise and Effective Clinical Delivery?

by Erminia Romano, Jamie Honeychurch and Timothy M. Illidge

Cancers 2021, 13(3), 457; https://doi.org/10.3390/cancers13030457 - 26 Jan 2021

Cited by 30 | Viewed by 4691

Abstract

Radiotherapy (RT) is highly effective at directly killing tumor cells and plays an important part in cancer treatments being delivered to around 50% of all cancer patients. The additional immunomodulatory properties of RT have been investigated, and if exploited effectively, have the potential to further improve the efficacy of RT and cancer outcomes. The initial results of combining RT with immunomodulatory agents have generated promising data in pre-clinical studies, which has in turn led to a large number of RT and immunotherapy clinical trials. The overarching aim of these combinations is to enhance anti-tumor immune responses and improve responses rates and patient outcomes. In order to maximize this undoubted opportunity, there remain a number of important questions that need to be addressed, including: (i) the optimal RT dose and fractionation schedule; (ii) the optimal RT target volume; (iii) the optimal immuno-oncology (IO) agent(s) to partner with RT; (iv) the optimal site(s)/route(s) of administration of IO agents; and finally, the optimal RT schedule. In this review, we will summarize progress to date and identify current gaps in knowledge that need to be addressed in order to facilitate effective clinical translation of RT and IO agent combinations. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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21 pages, 1597 KiB

Open AccessReview

Regional Responses in Radiation-Induced Normal Tissue Damage

by Daniëlle C. Voshart, Julia Wiedemann, Peter van Luijk and Lara Barazzuol

Cancers 2021, 13(3), 367; https://doi.org/10.3390/cancers13030367 - 20 Jan 2021

Cited by 32 | Viewed by 4534

Abstract

Normal tissue side effects remain a major concern in radiotherapy. The improved precision of radiation dose delivery of recent technological developments in radiotherapy has the potential to reduce the radiation dose to organ regions that contribute the most to the development of side effects. This review discusses the contribution of regional variation in radiation responses in several organs. In the brain, various regions were found to contribute to radiation-induced neurocognitive dysfunction. In the parotid gland, the region containing the major ducts was found to be critical in hyposalivation. The heart and lung were each found to exhibit regional responses while also mutually affecting each other’s response to radiation. Sub-structures critical for the development of side effects were identified in the pancreas and bladder. The presence of these regional responses is based on a non-uniform distribution of target cells or sub-structures critical for organ function. These characteristics are common to most organs in the body and we therefore hypothesize that regional responses in radiation-induced normal tissue damage may be a shared occurrence. Further investigations will offer new opportunities to reduce normal tissue side effects of radiotherapy using modern and high-precision technologies. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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18 pages, 1664 KiB

Open AccessReview

Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas

by Henriette Pedersen, Kjeld Schmiegelow and Petra Hamerlik

Cancers 2020, 12(10), 2813; https://doi.org/10.3390/cancers12102813 - 30 Sep 2020

Cited by 22 | Viewed by 4523

Abstract

Malignant gliomas (MG) are among the most prevalent and lethal primary intrinsic brain tumors. Although radiotherapy (RT) is the most effective nonsurgical therapy, recurrence is universal. Dysregulated DNA damage response pathway (DDR) signaling, rampant genomic instability, and radio-resistance are among the hallmarks of MGs, with current therapies only offering palliation. A subgroup of pediatric high-grade gliomas (pHGG) is characterized by H3K27M mutation, which drives global loss of di- and trimethylation of histone H3K27. Here, we review the most recent literature and discuss the key studies dissecting the molecular biology of H3K27M-mutated gliomas in children. We speculate that the aberrant activation and/or deactivation of some of the key components of DDR may be synthetically lethal to H3K27M mutation and thus can open novel avenues for effective therapeutic interventions for patients suffering from this deadly disease. Full article

(This article belongs to the Special Issue Advances in Experimental Radiotherapy)

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