Particle Therapy to Overcome Cancer Radiation Resistance: "ARCHADE" Consortium Updates in Radiation Biology

Abstract

Radiation therapy is a medical treatment that uses high doses of radiation to kill or damage cancer cells. It works by damaging the DNA within the cancer cells, ultimately causing cell death. Radiotherapy can be used as a primary treatment, adjuvant treatment in combination with surgery or chemotherapy or palliative treatment to relieve symptoms in advanced cancer stages. Radiation therapy is constantly improving in order to enhance the effect on cancer cells and reduce the side effects on healthy tissues. Our results clearly demonstrate that proton therapy and, even more, carbon ion therapy appear as promising alternatives to overcome the radioresistance of various tumors thanks to less dependency on oxygen and a better ability to kill cancer stem cells. Interestingly, hadrons also retain the advantages of radiosensitization approaches. These data confirm the great ability of hadrons to spare healthy tissue near the tumor via various mechanisms (reduced lymphopenia, bystander effect, etc.). Technology and machine improvements such as image-guided radiotherapy or particle therapies can improve treatment quality and efficacy (dose deposition and biological effect) in tumors while increasingly sparing healthy tissues. Radiation biology can help to understand how cancer cells resist radiation (hypoxia, DNA repair mechanisms, stem cell status, cell cycle position, etc.), how normal tissues may display sensitivity to radiation and how radiation effects can be increased with either radiosensitizers or accelerated particles. All these research topics are under investigation within the ARCHADE research community in France. By focusing on these areas, radiotherapy can become more effective, targeted and safe, enhancing the overall treatment experience and outcomes for cancer patients. Our goal is to provide biological evidence of the therapeutic advantages of hadrontherapy, according to the tumor characteristics. This article aims to give an updated view of our research in radiation biology within the frame of the French "ARCHADE association" and new perspectives on research and treatment with the C400 multi-ions accelerator prototype.

Keywords: bystander effect; cancer stem cells; carbon ion therapy; hadrontherapy; hypoxia; normal tissues; radiation resistance; radiosensitizers.

Figure 1

Hypoxia induces a GB cell type-dependent radioresistance to C-ion irradiation; reprinted with permission from [12], Copyright 2020MDPI. (A,B) Representative photographs of the cell morphology observed 72 h after C-ion irradiation in normoxia or hypoxia (4 Gy, C-ions 28 keV/µm) for U251 cells ((A) top part) and GL15 cells ((B) top part). Survival curves from clonogenic assays performed in normoxic (21% O₂) or hypoxic conditions (1% O₂) after X-rays or C-ions (28 keV/µm) for U251 cells ((A) down part) and GL15 cells ((B)-down part). Fisher’s LSD post-hoc test after a significant two-way ANOVA (group and dose effects): * p < 0.05, ** p < 0.01 vs. normoxia for X-rays or C-ion irradiation; # p < 0.05, ### p < 0.0001 vs. X-rays in normoxia or hypoxia. (C) Quantification of radiobiological parameters obtained from X-rays or C-ion irradiations for U251 cells and (D) GL15 cells grown in normoxic or hypoxic conditions. For SF2, D37 and D10: * p < 0.05 vs. normoxia for X-rays or C-ion irradiation (Fisher’s LSD post-hoc test after a significant one-way ANOVA). For RBE: # p < 0.05 vs. theoretical value = 1 (univariate t-test) and * p < 0.05 vs. normoxia (Student’s t-test). For OER: # p < 0.05 vs. theoretical value = 1 (univariate t-test) and $$ p < 0.01 vs. X-rays (Student’s t-test). All data of the figure are presented by mean ± SD; all experiments performed in triplicate (n = 3) for both irradiation and oxygen conditions.

Figure 2

Sensitization of radioresistant CHS cells with the core–shell doxorubicin-loaded nanoparticles and X-ray, proton and C-ion radiations. Core–shell iron oxide (Fe₃O₄) nanoparticles (IONP) were encapsulated in polyethylene glycol (PEG) and loaded with doxorubicin (DOX). ↑: increase; ↓: decrease.

Figure 3

Analysis of the direct effects of radiation on the structure, stability and biological activity of collagen-fragmentation peptides. Collagen mimetic peptides, with a triple-helical structure were submitted to ionizing radiation (C-ions and X-rays) in gas-phase condition (1). Following triple-helix dissociation (2), chain fragmentation and small peptide formation (Pro–Pro–Gly) were observed (3) with a preferential cleavage sites on the glycine–proline peptidic bond. The resulting peptides from radiation-induced collagen-fragmentation were analyzed on chondrocytes culture and displayed a matrikine-like biological activity (4).