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Novel Radiotherapeutic Approaches: Molecular Aspects and Radiobiological Mechanisms

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 9512

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Special Issue Editor

Prof. Dr. Loredana Marcu

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Guest Editor

1. Faculty of Informatics & Science, University of Oradea, 410087 Oradea, Romania
2. UniSA Allied Health and Human Performance, University of South Australia, Adelaide 5000, Australia
Interests: modelling of tumour growth and development; risk of second cancer; personalised radiotherapy; treatment resistance; radiobiology
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Special Issue Information

Dear Colleagues,

Without doubt, radiotherapy has seen noteworthy developments over the last few decades. Nonetheless, therapies with a significant impact on tumour control or sparing of normal tissues are still in their preclinical stages or waiting for clinical validation. Similar to the transition from standard (2Gy/fraction) to altered fractionation schedules, radiotherapy delivery has undergone important evolutions from conventional to nonconventional administration.

FLASH radiotherapy is a novel, nonconventional irradiation technique that delivers ultra-high dose rates to the target, with excellent normal tissue sparing. While the mechanisms behind the enhancement of the therapeutic window owing to FLASH are not fully elucidated, there is considerable in vivo evidence that highlights the advantages of ultra-high dose rates compared to traditional radiotherapy.

High-dose, spatially fractionated radiation also known as GRID therapy has been clinically evaluated over the last few decades using various grid designs to allow for a non-uniform dose delivery. With a similar concept, a more recently developed nonconventional irradiation technique employing minibeams via an array of closely spaced beams is appraised. This form of beam settings is thought to influence cell signalling via abscopal effects, leading to the difference in response between malignant and healthy cells.

Delivery of nonconventional radiotherapy has been trialled with photons, electrons and proton beams alike. While showing real potential to widen the therapeutic window, these techniques require better understanding of the radiobiological and physicochemical properties for further optimisation.

The aim of this Special Issue is to encompass both review articles and original research on the molecular and radiobiological aspects behind the success of nonconventional radiation delivery, including radiobiological modelling and laboratory research.

Prof. Dr. Loredana Marcu
Guest Editor

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Keywords

nonconventional radiotherapy
FLASH effect
ultra-high dose rate
minibeam
GRID radiotherapy
spatially fractionated irradiation
normal tissue sparing

Published Papers (3 papers)

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Research

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18 pages, 2177 KiB

Open AccessArticle

Modulating Nucleus Oxygen Concentration by Altering Intramembrane Cholesterol Levels: Creating Hypoxic Nucleus in Oxic Conditions

by Joao Seco, Clarence C. King, Gianmarco Camazzola, Jeannette Jansen, Luca Tirinato, Maria G. Marafioti, Rachel Hanley, Francesca Pagliari and Scott P. Beckman

Int. J. Mol. Sci. 2022, 23(9), 5077; https://doi.org/10.3390/ijms23095077 - 3 May 2022

Cited by 2 | Viewed by 3038

Abstract

We propose a novel mechanism by which cancer cells can modulate the oxygen concentration within the nucleus, potentially creating low nuclear oxygen conditions without the need of an hypoxic micro-environment and suited for allowing cancer cells to resist chemo- and radio-therapy. The cells ability to alter intra-cellular oxygen conditions depends on the amount of cholesterol present within the cellular membranes, where high levels of cholesterol can yield rigid membranes that slow oxygen diffusion. The proposed mechanism centers on the competition between (1) the diffusion of oxygen within the cell and across cellular membranes that replenishes any consumed oxygen and (2) the consumption of oxygen in the mitochondria, peroxisomes, endoplasmic reticulum (ER), etc. The novelty of our work centers around the assumption that the cholesterol content of a membrane can affect the oxygen diffusion across the membrane, reducing the cell ability to replenish the oxygen consumed within the cell. For these conditions, the effective diffusion rate of oxygen becomes of the same order as the oxygen consumption rate, allowing the cell to reduce the oxygen concentration of the nucleus, with implications to the Warburg Effect. The cellular and nucleus oxygen content is indirectly evaluated experimentally for bladder (T24) cancer cells and during the cell cycle, where the cells are initially synchronized using hydroxeaurea (HU) at the late G1-phase/early S-phase. The analysis of cellular and nucleus oxygen concentration during cell cycle is performed via (i) RT-qPCR gene analysis of hypoxia inducible transcription factors (HIF) and prolyl hydroxylases (PHD) and (ii) radiation clonogenic assay every 2 h, after release from synchronization. The HIF/PHD genes allowed us to correlate cellular oxygen with oxygen concentration in the nucleus that is obtained from the cells radiation response, where the amount DNA damage due to radiation is directly related to the amount of oxygen present in the nucleus. We demonstrate that during the S-phase cells can become hypoxic in the late S-phase/early G2-phase and therefore the radiation resistance increases 2- to 3-fold. Full article

(This article belongs to the Special Issue Novel Radiotherapeutic Approaches: Molecular Aspects and Radiobiological Mechanisms)

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Review

Jump to: Research

20 pages, 888 KiB

Open AccessReview

Potential Molecular Mechanisms behind the Ultra-High Dose Rate “FLASH” Effect

by Eva Bogaerts, Ellina Macaeva, Sofie Isebaert and Karin Haustermans

Int. J. Mol. Sci. 2022, 23(20), 12109; https://doi.org/10.3390/ijms232012109 - 11 Oct 2022

Cited by 7 | Viewed by 2354

Abstract

FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation—the FLASH effect—has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates. Full article

(This article belongs to the Special Issue Novel Radiotherapeutic Approaches: Molecular Aspects and Radiobiological Mechanisms)

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21 pages, 824 KiB

Open AccessReview

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy

by Leyla Moghaddasi, Paul Reid, Eva Bezak and Loredana G. Marcu

Int. J. Mol. Sci. 2022, 23(6), 3366; https://doi.org/10.3390/ijms23063366 - 20 Mar 2022

Cited by 16 | Viewed by 3443

Abstract

The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams. Full article

(This article belongs to the Special Issue Novel Radiotherapeutic Approaches: Molecular Aspects and Radiobiological Mechanisms)

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