International Journal of Molecular Sciences

Research

Jump to: Review

17 pages, 2258 KiB

Open AccessArticle

Immunologic Effects of Stereotactic Body Radiotherapy in Dogs with Spontaneous Tumors and the Impact of Intratumoral OX40/TLR Agonist Immunotherapy

by Mary-Keara Boss, Remy Watts, Lauren G. Harrison, Sophie Hopkins, Lyndah Chow, Erin Trageser, Carina Easton, Susan M. LaRue, Daniel Regan, Mark W. Dewhirst and Steven Dow

Int. J. Mol. Sci. 2022, 23(2), 826; https://doi.org/10.3390/ijms23020826 - 13 Jan 2022

Cited by 11 | Viewed by 3379

Abstract

Stereotactic body radiotherapy (SBRT) is known to induce important immunologic changes within the tumor microenvironment (TME). However, little is known regarding the early immune responses within the TME in the first few weeks following SBRT. Therefore, we used the canine spontaneous tumor model [...] Read more.

Stereotactic body radiotherapy (SBRT) is known to induce important immunologic changes within the tumor microenvironment (TME). However, little is known regarding the early immune responses within the TME in the first few weeks following SBRT. Therefore, we used the canine spontaneous tumor model to investigate TME responses to SBRT, and how local injection of immune modulatory antibodies to OX40 and TLR 3/9 agonists might modify those responses. Pet dogs with spontaneous cancers (melanoma, carcinoma, sarcoma, n = 6 per group) were randomized to treatment with either SBRT or SBRT combined with local immunotherapy. Serial tumor biopsies and serum samples were analyzed for immunologic responses. SBRT alone resulted at two weeks after treatment in increased tumor densities of CD3+ T cells, FoxP3+ Tregs, and CD204+ macrophages, and increased expression of genes associated with immunosuppression. The addition of OX40/TLR3/9 immunotherapy to SBRT resulted in local depletion of Tregs and tumor macrophages and reduced Treg-associated gene expression (FoxP3), suppressed macrophage-associated gene expression (IL-8), and suppressed exhausted T cell-associated gene expression (CTLA4). Increased concentrations of IL-7, IL-15, and IL-18 were observed in serum of animals treated with SBRT and immunotherapy, compared to animals treated with SBRT. A paradoxical decrease in the density of effector CD3+ T cells was observed in tumor tissues that received combined SBRT and immunotherapy as compared to animals treated with SBRT only. In summary, these results obtained in a spontaneous large animal cancer model indicate that addition of OX40/TLR immunotherapy to SBRT modifies important immunological effects both locally and systemically. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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14 pages, 4694 KiB

Open AccessArticle

Inhibition of Wnt/β-Catenin Signaling Sensitizes Esophageal Cancer Cells to Chemoradiotherapy

by Melanie Spitzner, Georg Emons, Karl Burkhard Schütz, Hendrik A. Wolff, Stefan Rieken, B. Michael Ghadimi, Günter Schneider and Marian Grade

Int. J. Mol. Sci. 2021, 22(19), 10301; https://doi.org/10.3390/ijms221910301 - 24 Sep 2021

Cited by 14 | Viewed by 2482

Abstract

The standard treatment of locally advanced esophageal cancer comprises multimodal treatment concepts including preoperative chemoradiotherapy (CRT) followed by radical surgical resection. However, despite intensified treatment approaches, 5-year survival rates are still low. Therefore, new strategies are required to overcome treatment resistance, and to [...] Read more.

The standard treatment of locally advanced esophageal cancer comprises multimodal treatment concepts including preoperative chemoradiotherapy (CRT) followed by radical surgical resection. However, despite intensified treatment approaches, 5-year survival rates are still low. Therefore, new strategies are required to overcome treatment resistance, and to improve patients’ outcome. In this study, we investigated the impact of Wnt/β-catenin signaling on CRT resistance in esophageal cancer cells. Experiments were conducted in adenocarcinoma and squamous cell carcinoma cell lines with varying expression levels of Wnt proteins and Wnt/β-catenin signaling activities. To investigate the effect of Wnt/β-catenin signaling on CRT responsiveness, we genetically or pharmacologically inhibited Wnt/β-catenin signaling. Our experiments revealed that inhibition of Wnt/β-catenin signaling sensitizes cell lines with robust pathway activity to CRT. In conclusion, Wnt/β-catenin activity may guide precision therapies in esophageal carcinoma patients. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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15 pages, 2505 KiB

Open AccessArticle

Local Interleukin-12 Treatment Enhances the Efficacy of Radiation Therapy by Overcoming Radiation-Induced Immune Suppression

by Ching-Fang Yu, Chun-Hsiang Chang, Chun-Chieh Wang, Ji-Hong Hong, Chi-Shiun Chiang and Fang-Hsin Chen

Int. J. Mol. Sci. 2021, 22(18), 10053; https://doi.org/10.3390/ijms221810053 - 17 Sep 2021

Cited by 4 | Viewed by 2497

Abstract

Radiation therapy (RT) recruits myeloid cells, leading to an immunosuppressive microenvironment that impedes its efficacy against tumors. Combination of immunotherapy with RT is a potential approach to reversing the immunosuppressive condition and enhancing tumor control after RT. This study aimed to assess the [...] Read more.

Radiation therapy (RT) recruits myeloid cells, leading to an immunosuppressive microenvironment that impedes its efficacy against tumors. Combination of immunotherapy with RT is a potential approach to reversing the immunosuppressive condition and enhancing tumor control after RT. This study aimed to assess the effects of local interleukin-12 (IL-12) therapy on improving the efficacy of RT in a murine prostate cancer model. Combined treatment effectively shrunk the radioresistant tumors by inducing a T helper-1 immune response and influx of CD8+ T cells. It also delayed the radiation-induced vascular damage accompanied by increased α-smooth muscle actin-positive pericyte coverage and blood perfusion. Moreover, RT significantly reduced the IL-12-induced levels of alanine aminotransferase in blood. However, it did not further improve the IL-12-induced anti-tumor effect on distant tumors. Upregulated expression of T-cell exhaustion-associated genes was found in tumors treated with IL-12 only and combined treatment, suggesting that T-cell exhaustion is potentially correlated with tumor relapse in combined treatment. In conclusion, this study illustrated that combination of radiation and local IL-12 therapy enhanced the host immune response and promoted vascular maturation and function. Furthermore, combination treatment was associated with less systemic toxicity than IL-12 alone, providing a potential option for tumor therapy in clinical settings. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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21 pages, 19853 KiB

Open AccessArticle

Fractionated Irradiation of Right Thorax Induces Abscopal Damage on Bone Marrow Cells via TNF-α and SAA

by Yimeng Song, Songling Hu, Junling Zhang, Lin Zhu, Xinrui Zhao, Qianping Chen, Jianghong Zhang, Yang Bai, Yan Pan and Chunlin Shao

Int. J. Mol. Sci. 2021, 22(18), 9964; https://doi.org/10.3390/ijms22189964 - 15 Sep 2021

Cited by 9 | Viewed by 2511

Abstract

Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of [...] Read more.

Radiation-induced abscopal effect (RIAE) outside of radiation field is becoming more attractive. However, the underlying mechanisms are still obscure. This work investigated the deleterious effect of thoracic irradiation (Th-IR) on distant bone marrow and associated signaling factors by irradiating the right thorax of mice with fractionated doses (8 Gy × 3). It was found that this localized Th-IR increased apoptosis of bone marrow cells and micronucleus formation of bone marrow polychromatic erythrocytes after irradiation. Tandem mass tagging (TMT) analysis and ELISA assay showed that the concentrations of TNF-α and serum amyloid A (SAA) in the mice were significantly increased after Th-IR. An immunohistochemistry assay revealed a robust increase in SAA expression in the liver rather than in the lungs after Th-IR. In vitro experiments demonstrated that TNF-α induced SAA expression in mouse hepatoma Hepa1–6 cells, and these two signaling factors induced DNA damage in bone marrow mesenchymal stem cells (BMSCs) by increasing reactive oxygen species (ROS). On the other hand, injection with TNF-α inhibitor before Th-IR reduced the secretion of SAA and attenuated the abscopal damage in bone marrow. ROS scavenger NAC could also mitigated Th-IR/SAA-induced bone marrow damage in mice. Our findings indicated that Th-IR triggered TNF-α release from lung, which further promoted SAA secretion from liver in a manner of cascade reaction. Consequently, these signaling factors resulted in induction of abscopal damage on bone marrow of mice. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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Review

Jump to: Research

13 pages, 3179 KiB

Open AccessReview

EGFR Mutations in Head and Neck Squamous Cell Carcinoma

by Sindhu Nair, James A. Bonner and Markus Bredel

Int. J. Mol. Sci. 2022, 23(7), 3818; https://doi.org/10.3390/ijms23073818 - 30 Mar 2022

Cited by 35 | Viewed by 4228

Abstract

EGFR is a prototypical receptor tyrosine kinase that is overexpressed in multiple cancers including head and neck squamous cell carcinoma (HNSCC). The standard of care for HNSCC remains largely unchanged despite decades of research. While EGFR blockade is an attractive target in HNSCC [...] Read more.

EGFR is a prototypical receptor tyrosine kinase that is overexpressed in multiple cancers including head and neck squamous cell carcinoma (HNSCC). The standard of care for HNSCC remains largely unchanged despite decades of research. While EGFR blockade is an attractive target in HNSCC patients and anti-EGFR strategies including monoclonal antibodies and kinase inhibitors have shown some clinical benefit, efficacy is often due to the eventual development of resistance. In this review, we discuss how the acquisition of mutations in various domains of the EGFR gene not only alter drug binding dynamics giving rise to resistance, but also how mutations can impact radiation response and overall survival in HNSCC patients. A better understanding of the EGFR mutational landscape and its dynamic effects on treatment resistance hold the potential to better stratify patients for targeted therapies in order to maximize therapeutic benefits. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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11 pages, 1764 KiB

Open AccessReview

Exploiting Radiation Induction of Antigens in Cancer: Targeted Drug Delivery

by Vaishali Kapoor, Abhay K. Singh, Calvin D. Lewis, Sapna Deore and Dennis E. Hallahan

Int. J. Mol. Sci. 2022, 23(6), 3041; https://doi.org/10.3390/ijms23063041 - 11 Mar 2022

Cited by 4 | Viewed by 3111

Abstract

Therapeutic antibodies used to treat cancer are effective in patients with advanced-stage disease. For example, antibodies that activate T-lymphocytes improve survival in many cancer subtypes. In addition, antibody–drug conjugates effectively target cytotoxic agents that are specific to cancer. This review discusses radiation-inducible antigens, [...] Read more.

Therapeutic antibodies used to treat cancer are effective in patients with advanced-stage disease. For example, antibodies that activate T-lymphocytes improve survival in many cancer subtypes. In addition, antibody–drug conjugates effectively target cytotoxic agents that are specific to cancer. This review discusses radiation-inducible antigens, which are stress-regulated proteins that are over-expressed in cancer. These inducible cell surface proteins become accessible to antibody binding during the cellular response to genotoxic stress. The lead antigens are induced in all histologic subtypes and nearly all advanced-stage cancers, but show little to no expression in normal tissues. Inducible antigens are exploited by using therapeutic antibodies that bind specifically to these stress-regulated proteins. Antibodies that bind to the inducible antigens GRP78 and TIP1 enhance the efficacy of radiotherapy in preclinical cancer models. The conjugation of cytotoxic drugs to the antibodies further improves cancer response. This review focuses on the use of radiotherapy to control the cancer-specific binding of therapeutic antibodies and antibody–drug conjugates. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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25 pages, 1116 KiB

Open AccessReview

Overcoming Radiation Resistance in Gliomas by Targeting Metabolism and DNA Repair Pathways

by Wei Meng, Joshua D. Palmer, Michael Siedow, Saikh Jaharul Haque and Arnab Chakravarti

Int. J. Mol. Sci. 2022, 23(4), 2246; https://doi.org/10.3390/ijms23042246 - 17 Feb 2022

Cited by 11 | Viewed by 4004

Abstract

Gliomas represent a wide spectrum of brain tumors characterized by their high invasiveness, resistance to chemoradiotherapy, and both intratumoral and intertumoral heterogeneity. Recent advances in transomics studies revealed that enormous abnormalities exist in different biological layers of glioma cells, which include genetic/epigenetic alterations, [...] Read more.

Gliomas represent a wide spectrum of brain tumors characterized by their high invasiveness, resistance to chemoradiotherapy, and both intratumoral and intertumoral heterogeneity. Recent advances in transomics studies revealed that enormous abnormalities exist in different biological layers of glioma cells, which include genetic/epigenetic alterations, RNA expressions, protein expression/modifications, and metabolic pathways, which provide opportunities for development of novel targeted therapeutic agents for gliomas. Metabolic reprogramming is one of the hallmarks of cancer cells, as well as one of the oldest fields in cancer biology research. Altered cancer cell metabolism not only provides energy and metabolites to support tumor growth, but also mediates the resistance of tumor cells to antitumor therapies. The interactions between cancer metabolism and DNA repair pathways, and the enhancement of radiotherapy sensitivity and assessment of radiation response by modulation of glioma metabolism are discussed herein. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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17 pages, 933 KiB

Open AccessReview

Leveraging Blood-Based Diagnostics to Predict Tumor Biology and Extend the Application and Personalization of Radiotherapy in Liver Cancers

by Franziska Hauth, Hannah J. Roberts, Theodore S. Hong and Dan G. Duda

Int. J. Mol. Sci. 2022, 23(4), 1926; https://doi.org/10.3390/ijms23041926 - 9 Feb 2022

Cited by 2 | Viewed by 2698

Abstract

While the incidence of primary liver cancers has been increasing worldwide over the last few decades, the mortality has remained consistently high. Most patients present with underlying liver disease and have limited treatment options. In recent years, radiotherapy has emerged as a promising [...] Read more.

While the incidence of primary liver cancers has been increasing worldwide over the last few decades, the mortality has remained consistently high. Most patients present with underlying liver disease and have limited treatment options. In recent years, radiotherapy has emerged as a promising approach for some patients; however, the risk of radiation induced liver disease (RILD) remains a limiting factor for some patients. Thus, the discovery and validation of biomarkers to measure treatment response and toxicity is critical to make progress in personalizing radiotherapy for liver cancers. While tissue biomarkers are optimal, hepatocellular carcinoma (HCC) is typically diagnosed radiographically, making tumor tissue not readily available. Alternatively, blood-based diagnostics may be a more practical option as blood draws are minimally invasive, widely availability and may be performed serially during treatment. Possible blood-based diagnostics include indocyanine green test, plasma or serum levels of HGF or cytokines, circulating blood cells and genomic biomarkers. The albumin–bilirubin (ALBI) score incorporates albumin and bilirubin to subdivide patients with well-compensated underlying liver dysfunction (Child–Pugh score A) into two distinct groups. This review provides an overview of the current knowledge on circulating biomarkers and blood-based scores in patients with malignant liver disease undergoing radiotherapy and outlines potential future directions. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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14 pages, 640 KiB

Open AccessReview

Interactions between Radiation and One-Carbon Metabolism

by Navyateja Korimerla and Daniel R. Wahl

Int. J. Mol. Sci. 2022, 23(3), 1919; https://doi.org/10.3390/ijms23031919 - 8 Feb 2022

Cited by 6 | Viewed by 5219

Abstract

Metabolic reprogramming is a hallmark of cancer. Cancer cells rewire one-carbon metabolism, a central metabolic pathway, to turn nutritional inputs into essential biomolecules required for cancer cell growth and maintenance. Radiation therapy, a common cancer therapy, also interacts and alters one-carbon metabolism. This [...] Read more.

Metabolic reprogramming is a hallmark of cancer. Cancer cells rewire one-carbon metabolism, a central metabolic pathway, to turn nutritional inputs into essential biomolecules required for cancer cell growth and maintenance. Radiation therapy, a common cancer therapy, also interacts and alters one-carbon metabolism. This review discusses the interactions between radiation therapy, one-carbon metabolism and its component metabolic pathways. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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23 pages, 3125 KiB

Open AccessReview

Understanding Molecular Mechanisms and Identifying Key Processes in Chronic Radiation Cystitis

by Clément Brossard, Anne-Charlotte Lefranc, Jean-Marc Simon, Marc Benderitter, Fabien Milliat and Alain Chapel

Int. J. Mol. Sci. 2022, 23(3), 1836; https://doi.org/10.3390/ijms23031836 - 6 Feb 2022

Cited by 10 | Viewed by 3898

Abstract

Chronic radiation cystitis (CRC) is a consequence of pelvic radiotherapy and affects 5–10% of patients. The pathology of CRC is without curative treatment and is characterized by incontinence, pelvic pain and hematuria, which severely degrades patients’ quality of life. Current management strategies rely [...] Read more.

Chronic radiation cystitis (CRC) is a consequence of pelvic radiotherapy and affects 5–10% of patients. The pathology of CRC is without curative treatment and is characterized by incontinence, pelvic pain and hematuria, which severely degrades patients’ quality of life. Current management strategies rely primarily on symptomatic measures and have certain limitations. Thanks to a better understanding of the pathophysiology of radiation cystitis, studies targeting key manifestations such as inflammation, neovascularization and cell atrophy have emerged and are promising avenues for future treatment. However, the mechanisms of CRC are still better described in animal models than in human models. Preclinical studies conducted to elucidate the pathophysiology of CRC use distinct models and are most often limited to specific processes, such as fibrosis, vascular damage and inflammation. This review presents a synthesis of experimental studies aimed at improving our understanding of the molecular mechanisms at play and identifying key processes in CRC. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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26 pages, 6700 KiB

Open AccessReview

Chronoradiobiology of Breast Cancer: The Time Is Now to Link Circadian Rhythm and Radiation Biology

by Nicolas Nelson, Joseph Lombardo, Lauren Matlack, Alexandria Smith, Kamryn Hines, Wenyin Shi and Nicole L. Simone

Int. J. Mol. Sci. 2022, 23(3), 1331; https://doi.org/10.3390/ijms23031331 - 25 Jan 2022

Cited by 16 | Viewed by 7577

Abstract

Circadian disruption has been linked to cancer development, progression, and radiation response. Clinical evidence to date shows that circadian genetic variation and time of treatment affect radiation response and toxicity for women with breast cancer. At the molecular level, there is interplay between [...] Read more.

Circadian disruption has been linked to cancer development, progression, and radiation response. Clinical evidence to date shows that circadian genetic variation and time of treatment affect radiation response and toxicity for women with breast cancer. At the molecular level, there is interplay between circadian clock regulators such as PER1, which mediates ATM and p53-mediated cell cycle gating and apoptosis. These molecular alterations may govern aggressive cancer phenotypes, outcomes, and radiation response. Exploiting the various circadian clock mechanisms may enhance the therapeutic index of radiation by decreasing toxicity, increasing disease control, and improving outcomes. We will review the body’s natural circadian rhythms and clock gene-regulation while exploring preclinical and clinical evidence that implicates chronobiological disruptions in the etiology of breast cancer. We will discuss radiobiological principles and the circadian regulation of DNA damage responses. Lastly, we will present potential rational therapeutic approaches that target circadian pathways to improve outcomes in breast cancer. Understanding the implications of optimal timing in cancer treatment and exploring ways to entrain circadian biology with light, diet, and chronobiological agents like melatonin may provide an avenue for enhancing the therapeutic index of radiotherapy. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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15 pages, 16575 KiB

Open AccessReview

A Century of Fractionated Radiotherapy: How Mathematical Oncology Can Break the Rules

by Nima Ghaderi, Joseph Jung, Sarah C. Brüningk, Ajay Subramanian, Lauren Nassour and Jeffrey Peacock

Int. J. Mol. Sci. 2022, 23(3), 1316; https://doi.org/10.3390/ijms23031316 - 24 Jan 2022

Cited by 12 | Viewed by 4439

Abstract

Radiotherapy is involved in 50% of all cancer treatments and 40% of cancer cures. Most of these treatments are delivered in fractions of equal doses of radiation (Fractional Equivalent Dosing (FED)) in days to weeks. This treatment paradigm has remained unchanged in the [...] Read more.

Radiotherapy is involved in 50% of all cancer treatments and 40% of cancer cures. Most of these treatments are delivered in fractions of equal doses of radiation (Fractional Equivalent Dosing (FED)) in days to weeks. This treatment paradigm has remained unchanged in the past century and does not account for the development of radioresistance during treatment. Even if under-optimized, deviating from a century of successful therapy delivered in FED can be difficult. One way of exploring the infinite space of fraction size and scheduling to identify optimal fractionation schedules is through mathematical oncology simulations that allow for in silico evaluation. This review article explores the evidence that current fractionation promotes the development of radioresistance, summarizes mathematical solutions to account for radioresistance, both in the curative and non-curative setting, and reviews current clinical data investigating non-FED fractionated radiotherapy. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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16 pages, 1604 KiB

Open AccessReview

Personalized Nutrition as a Key Contributor to Improving Radiation Response in Breast Cancer

by Anuradha A. Shastri, Joseph Lombardo, Samantha C. Okere, Stephanie Higgins, Brittany C. Smith, Tiziana DeAngelis, Ajay Palagani, Kamryn Hines, Daniel A. Monti, Stella Volpe, Edith P. Mitchell and Nicole L. Simone

Int. J. Mol. Sci. 2022, 23(1), 175; https://doi.org/10.3390/ijms23010175 - 24 Dec 2021

Cited by 7 | Viewed by 4219

Abstract

Understanding metabolic and immune regulation inherent to patient populations is key to improving the radiation response for our patients. To date, radiation therapy regimens are prescribed based on tumor type and stage. Patient populations who are noted to have a poor response to [...] Read more.

Understanding metabolic and immune regulation inherent to patient populations is key to improving the radiation response for our patients. To date, radiation therapy regimens are prescribed based on tumor type and stage. Patient populations who are noted to have a poor response to radiation such as those of African American descent, those who have obesity or metabolic syndrome, or senior adult oncology patients, should be considered for concurrent therapies with radiation that will improve response. Here, we explore these populations of breast cancer patients, who frequently display radiation resistance and increased mortality rates, and identify the molecular underpinnings that are, in part, responsible for the radiation response and that result in an immune-suppressive tumor microenvironment. The resulting immune phenotype is discussed to understand how antitumor immunity could be improved. Correcting nutrient deficiencies observed in these populations should be considered as a means to improve the therapeutic index of radiation therapy. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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14 pages, 1455 KiB

Open AccessReview

Molecular Biology in Treatment Decision Processes—Neuro-Oncology Edition

by Andra V. Krauze and Kevin Camphausen

Int. J. Mol. Sci. 2021, 22(24), 13278; https://doi.org/10.3390/ijms222413278 - 10 Dec 2021

Cited by 1 | Viewed by 3204

Abstract

Computational approaches including machine learning, deep learning, and artificial intelligence are growing in importance in all medical specialties as large data repositories are increasingly being optimised. Radiation oncology as a discipline is at the forefront of large-scale data acquisition and well positioned towards [...] Read more.

Computational approaches including machine learning, deep learning, and artificial intelligence are growing in importance in all medical specialties as large data repositories are increasingly being optimised. Radiation oncology as a discipline is at the forefront of large-scale data acquisition and well positioned towards both the production and analysis of large-scale oncologic data with the potential for clinically driven endpoints and advancement of patient outcomes. Neuro-oncology is comprised of malignancies that often carry poor prognosis and significant neurological sequelae. The analysis of radiation therapy mediated treatment and the potential for computationally mediated analyses may lead to more precise therapy by employing large scale data. We analysed the state of the literature pertaining to large scale data, computational analysis, and the advancement of molecular biomarkers in neuro-oncology with emphasis on radiation oncology. We aimed to connect existing and evolving approaches to realistic avenues for clinical implementation focusing on low grade gliomas (LGG), high grade gliomas (HGG), management of the elderly patient with HGG, rare central nervous system tumors, craniospinal irradiation, and re-irradiation to examine how computational analysis and molecular science may synergistically drive advances in personalised radiation therapy (RT) and optimise patient outcomes. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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17 pages, 679 KiB

Open AccessReview

Regulation of the Cell-Intrinsic DNA Damage Response by the Innate Immune Machinery

by Thomas J. Hayman and Peter M. Glazer

Int. J. Mol. Sci. 2021, 22(23), 12761; https://doi.org/10.3390/ijms222312761 - 25 Nov 2021

Cited by 10 | Viewed by 2887

Abstract

Maintenance of genomic integrity is crucial for cell survival. As such, elegant DNA damage response (DDR) systems have evolved to ensure proper repair of DNA double-strand breaks (DSBs) and other lesions that threaten genomic integrity. Towards this end, most therapeutic studies have focused [...] Read more.

Maintenance of genomic integrity is crucial for cell survival. As such, elegant DNA damage response (DDR) systems have evolved to ensure proper repair of DNA double-strand breaks (DSBs) and other lesions that threaten genomic integrity. Towards this end, most therapeutic studies have focused on understanding of the canonical DNA DSB repair pathways to enhance the efficacy of DNA-damaging therapies. While these approaches have been fruitful, there has been relatively limited success to date and potential for significant normal tissue toxicity. With the advent of novel immunotherapies, there has been interest in understanding the interactions of radiation therapy with the innate and adaptive immune responses, with the ultimate goal of enhancing treatment efficacy. While a substantial body of work has demonstrated control of the immune-mediated (extrinsic) responses to DNA-damaging therapies by several innate immune pathways (e.g., cGAS–STING and RIG-I), emerging work demonstrates an underappreciated role of the innate immune machinery in directly regulating tumor cell-intrinsic/cell-autonomous responses to DNA damage. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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9 pages, 522 KiB

Open AccessReview

Contribution of Lipid Oxidation and Ferroptosis to Radiotherapy Efficacy

by Ashley N. Pearson, Joseph Carmicheal, Long Jiang, Yu Leo Lei and Michael D. Green

Int. J. Mol. Sci. 2021, 22(22), 12603; https://doi.org/10.3390/ijms222212603 - 22 Nov 2021

Cited by 19 | Viewed by 5482

Abstract

Radiotherapy promotes tumor cell death and senescence through the induction of oxidative damage. Recent work has highlighted the importance of lipid peroxidation for radiotherapy efficacy. Excessive lipid peroxidation can promote ferroptosis, a regulated form of cell death. In this review, we address the [...] Read more.

Radiotherapy promotes tumor cell death and senescence through the induction of oxidative damage. Recent work has highlighted the importance of lipid peroxidation for radiotherapy efficacy. Excessive lipid peroxidation can promote ferroptosis, a regulated form of cell death. In this review, we address the evidence supporting a role of ferroptosis in response to radiotherapy and discuss the molecular regulators that underlie this interaction. Finally, we postulate on the clinical implications for the intersection of ferroptosis and radiotherapy. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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21 pages, 1141 KiB

Open AccessReview

Bridging Radiotherapy to Immunotherapy: The IFN–JAK–STAT Axis

by Lewis Zhichang Shi and James A. Bonner

Int. J. Mol. Sci. 2021, 22(22), 12295; https://doi.org/10.3390/ijms222212295 - 14 Nov 2021

Cited by 19 | Viewed by 3996

Abstract

The unprecedented successes of immunotherapies (IOs) including immune checkpoint blockers (ICBs) and adoptive T-cell therapy (ACT) in patients with late-stage cancer provide proof-of-principle evidence that harnessing the immune system, in particular T cells, can be an effective approach to eradicate cancer. This instills [...] Read more.

The unprecedented successes of immunotherapies (IOs) including immune checkpoint blockers (ICBs) and adoptive T-cell therapy (ACT) in patients with late-stage cancer provide proof-of-principle evidence that harnessing the immune system, in particular T cells, can be an effective approach to eradicate cancer. This instills strong interests in understanding the immunomodulatory effects of radiotherapy (RT), an area that was actually investigated more than a century ago but had been largely ignored for many decades. With the “newly” discovered immunogenic responses from RT, numerous endeavors have been undertaken to combine RT with IOs, in order to bolster anti-tumor immunity. However, the underlying mechanisms are not well defined, which is a subject of much investigation. We therefore conducted a systematic literature search on the molecular underpinnings of RT-induced immunomodulation and IOs, which identified the IFN–JAK–STAT pathway as a major regulator. Our further analysis of relevant studies revealed that the signaling strength and duration of this pathway in response to RT and IOs may determine eventual immunological outcomes. We propose that strategic targeting of this axis can boost the immunostimulatory effects of RT and radiosensitizing effects of IOs, thereby promoting the efficacy of combination therapy of RT and IOs. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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17 pages, 9078 KiB

Open AccessReview

Liquid Biopsies for Molecular Biology-Based Radiotherapy

by Erik S. Blomain and Everett J. Moding

Int. J. Mol. Sci. 2021, 22(20), 11267; https://doi.org/10.3390/ijms222011267 - 19 Oct 2021

Cited by 6 | Viewed by 4135

Abstract

Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In [...] Read more.

Molecular alterations drive cancer initiation and evolution during development and in response to therapy. Radiotherapy is one of the most commonly employed cancer treatment modalities, but radiobiologic approaches for personalizing therapy based on tumor biology and individual risks remain to be defined. In recent years, analysis of circulating nucleic acids has emerged as a non-invasive approach to leverage tumor molecular abnormalities as biomarkers of prognosis and treatment response. Here, we evaluate the roles of circulating tumor DNA and related analyses as powerful tools for precision radiotherapy. We highlight emerging work advancing liquid biopsies beyond biomarker studies into translational research investigating tumor clonal evolution and acquired resistance. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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16 pages, 981 KiB

Open AccessReview

The Abscopal Effect: A Review of Pre-Clinical and Clinical Advances

by James R. Janopaul-Naylor, Yang Shen, David C. Qian and Zachary S. Buchwald

Int. J. Mol. Sci. 2021, 22(20), 11061; https://doi.org/10.3390/ijms222011061 - 14 Oct 2021

Cited by 72 | Viewed by 4927

Abstract

Radiotherapy has been used for more than a hundred years to cure or locally control tumors. Regression of tumors outside of the irradiated field was occasionally observed and is known as the abscopal effect. However, the occurrence of systemic anti-tumor effects was deemed [...] Read more.

Radiotherapy has been used for more than a hundred years to cure or locally control tumors. Regression of tumors outside of the irradiated field was occasionally observed and is known as the abscopal effect. However, the occurrence of systemic anti-tumor effects was deemed too rare and unpredictable to be a therapeutic goal. Recent studies suggest that immunotherapy and radiation in combination may enhance the abscopal response. Increasing numbers of cases are being reported since the routine implementation of immune checkpoint inhibitors, showing that combined radiotherapy with immunotherapy has a synergistic effect on both local and distant (i.e., unirradiated) tumors. In this review, we summarize pre-clinical and clinical reports, with a specific focus on the mechanisms behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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15 pages, 1131 KiB

Open AccessReview

Utilization of Pharmacological Ascorbate to Enhance Hydrogen Peroxide-Mediated Radiosensitivity in Cancer Therapy

by Zain Mehdi, Michael S. Petronek, Jeffrey M. Stolwijk, Kranti A. Mapuskar, Amanda L. Kalen, Garry R. Buettner, Joseph J. Cullen, Douglas R. Spitz, John M. Buatti and Bryan G. Allen

Int. J. Mol. Sci. 2021, 22(19), 10880; https://doi.org/10.3390/ijms221910880 - 8 Oct 2021

Cited by 13 | Viewed by 3788

Abstract

Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer [...] Read more.

Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer in cancer. The results of these studies are promising. This review summarizes data on pharmacological ascorbate (1) as a safe and efficacious adjuvant to cancer therapy; (2) as a selective radiosensitizer of cancer via a mechanism involving hydrogen peroxide; and (3) as a radioprotector in normal tissues. Additionally, we present new data demonstrating the ability of pharmacological ascorbate to enhance radiation-induced DNA damage in glioblastoma cells, facilitating cancer cell death. We propose that pharmacological ascorbate may be a general radiosensitizer in cancer therapy and simultaneously a radioprotector of normal tissue. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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14 pages, 788 KiB

Open AccessReview

Translation Initiation Machinery as a Tumor Selective Target for Radiosensitization

by Stacey L. Lehman, Evan D. Wilson, Kevin Camphausen and Philip J. Tofilon

Int. J. Mol. Sci. 2021, 22(19), 10664; https://doi.org/10.3390/ijms221910664 - 1 Oct 2021

Cited by 4 | Viewed by 3240

Abstract

Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in [...] Read more.

Towards improving the efficacy of radiotherapy, one approach is to target the molecules and processes mediating cellular radioresponse. Along these lines, translational control of gene expression has been established as a fundamental component of cellular radioresponse, which suggests that the molecules participating in this process (i.e., the translational machinery) can serve as determinants of radiosensitivity. Moreover, the proteins comprising the translational machinery are often overexpressed in tumor cells suggesting the potential for tumor specific radiosensitization. Studies to date have shown that inhibiting proteins involved in translation initiation, the rate-limiting step in translation, specifically the three members of the eIF4F cap binding complex eIF4E, eIF4G, and eIF4A as well as the cap binding regulatory kinases mTOR and Mnk1/2, results in the radiosensitization of tumor cells. Because ribosomes are required for translation initiation, inhibiting ribosome biogenesis also appears to be a strategy for radiosensitization. In general, the radiosensitization induced by targeting the translation initiation machinery involves inhibition of DNA repair, which appears to be the consequence of a reduced expression of proteins critical to radioresponse. The availability of clinically relevant inhibitors of this component of the translational machinery suggests opportunities to extend this approach to radiosensitization to patient care. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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9 pages, 266 KiB

Open AccessReview

Treatment of Cancer with Radio-Immunotherapy: What We Currently Know and What the Future May Hold

by William Tyler Turchan, Sean P. Pitroda and Ralph R. Weichselbaum

Int. J. Mol. Sci. 2021, 22(17), 9573; https://doi.org/10.3390/ijms22179573 - 3 Sep 2021

Cited by 11 | Viewed by 2932

Abstract

Radiotherapy and immunotherapy are most effective as cancer therapies in the setting of low-volume disease. Although initial studies of radio-immunotherapy in patients with metastatic cancer have not confirmed the efficacy of this approach, the role of radio-immunotherapy in patients with limited metastatic burden [...] Read more.

Radiotherapy and immunotherapy are most effective as cancer therapies in the setting of low-volume disease. Although initial studies of radio-immunotherapy in patients with metastatic cancer have not confirmed the efficacy of this approach, the role of radio-immunotherapy in patients with limited metastatic burden is unclear. We propose that further investigation of radio-immunotherapy in metastatic patients should focus upon patients with oligometastatic disease. Full article

(This article belongs to the Special Issue Radiation Biology and Molecular Radiation Oncology)

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