Models for Translational Proton Radiobiology—From Bench to Bedside and Back

Abstract

The number of proton therapy centers worldwide are increasing steadily, with more than two million cancer patients treated so far. Despite this development, pending questions on proton radiobiology still call for basic and translational preclinical research. Open issues are the on-going discussion on an energy-dependent varying proton RBE (relative biological effectiveness), a better characterization of normal tissue side effects and combination treatments with drugs originally developed for photon therapy. At the same time, novel possibilities arise, such as radioimmunotherapy, and new proton therapy schemata, such as FLASH irradiation and proton mini-beams. The study of those aspects demands for radiobiological models at different stages along the translational chain, allowing the investigation of mechanisms from the molecular level to whole organisms. Focusing on the challenges and specifics of proton research, this review summarizes the different available models, ranging from in vitro systems to animal studies of increasing complexity as well as complementing in silico approaches.

High-Throughput 3D Tumor Spheroid Array Platform for Evaluating Sensitivity of Proton-Drug Combinations

“…Theoretically, the treatment sequence could influence any combination data, including those without synergism of adavosertib and protons, and requires further validation. Recent studies have recommended that testing the drug efficacy in a single spheroid is desirable, because the data reproducibility of 3D models depends on morphological parameters such as volume and shape [ 36 , 37 ]. Thus, further morphological analysis of individual spheroids grown on a single pillar could provide valuable information.…”

Combined proton radiography and irradiation for high-precision preclinical studies in small animals

“…Proton therapy is an increasingly used treatment modality for cancer patients (1). However, open research questions, such as the variable relative biological effectiveness (RBE) along the proton beam or novel therapeutics, call for preclinical experiments in a clinical like setting (2)(3)(4). The irradiation of organ subvolumes and orthotopic tumors in small animals offers high translational value (2,5) and is in many aspects similar to clinical treatment, providing the right experimental conditions.…”

“…However, open research questions, such as the variable relative biological effectiveness (RBE) along the proton beam or novel therapeutics, call for preclinical experiments in a clinical like setting (2)(3)(4). The irradiation of organ subvolumes and orthotopic tumors in small animals offers high translational value (2,5) and is in many aspects similar to clinical treatment, providing the right experimental conditions. Amongst others, researchers need to consider down-scaling of the target volumes, accurate small-field dosimetry, beam energies, and how to integrate appropriate imaging modalities into their workflow (6).…”

Combined Systemic Drug Treatment with Proton Therapy: Investigations on Patient-Derived Organoids

“…While implementation of modern RT techniques decreased normal tissue toxicity [ 13 , 14 , 15 ], alternative radiation modalities such as proton therapy show further improvement concerning dose distribution compared to conventional photon irradiation [ 16 , 17 , 18 ]. A beneficial role of proton therapy in combination with CT was shown for PDAC [ 19 ], but there is not enough evidence to finally define the value of RCT in the field of proton therapy [ 20 , 21 ]. In clinical practice, combined RCT is applied in equal treatment schemes regardless of whether photons or protons are used.…”

“…Systematic studies to understand the relative biological effectiveness (RBE) of protons and the (possible differential) combination effects as well as the development of predictive biomarkers are considered to be among the important avenues in translational proton research [ 22 , 23 ]. For this purpose, the use of meaningful translational models is of utmost importance [ 20 ]. Patient-derived organoids (PDOs) are three-dimensional (3D) in vitro tumor models retaining the characteristics of their derived primary tissue [ 24 , 25 ].…”