Abstract
Proton therapy for cancer is now in widespread use, and facilities for carbon ion therapy are showing great promise, but a more complete understanding of the mechanisms underlying particle radiation therapy is still needed in order to optimize treatment. Studies of gene expression, especially those using whole genome techniques, can provide insight into many of the questions still remaining, from the molecular mechanisms involved to predicting patient outcome. This review will summarize gene expression studies of response to proton and carbon ion beams, as well as high-energy protons and high-z high-energy particles with relevance to particle therapy. In general, most such studies find that, in comparison with x-ray or gamma-ray exposure, particle irradiation increases both the number of genes responding and the magnitude of the response. Patterns of gene expression have suggested impacts on specific pathways of relevance to radiation therapy, such as enhancement or suppression of tumor progression or metastasis. However, even within the relatively small number of studies done to date there is no clear consensus of response, suggesting influence by multiple parameters, such as particle type, particle energy, and tumor type. Systematic gene expression studies can help to address these issues, and promoting a culture of data sharing will expedite the process, benefiting investigators across the radiation therapy field.
Highlights
Proton therapy has become increasingly widespread for cancer treatment, and there is strong interest in the development of treatment using heavier ions, with the current focus on carbon ions
As of March 2018, the Particle Therapy Co-Operative Group reported 68 proton therapy facilities worldwide and 11 carbon ion facilities already operating in Asia and Europe, with more under development
Another study compared the expression response of a panel of inflammation-associated genes in primary fibroblast cultures from 30 radiosensitive or radioresistant patients, and found that cells from sensitive patients had the greatest upregulation of inflammation genes with less dependence on radiation type [21]
Summary
Proton therapy has become increasingly widespread for cancer treatment, and there is strong interest in the development of treatment using heavier ions, with the current focus on carbon ions. Gene expression studies could help to address key questions in particle radiation therapy, including the impact of dose, dose rate, fractionation, hypoxia, and tumor type on the mechanisms of cell killing and immune activation as a function of LET Such studies could be exploited to identify druggable targets for optimizing combined therapy, and to develop predictive tests for individual sensitivity to particle therapy, both in terms of tumor response and normal tissue toxicity. Another study compared the expression response of a panel of inflammation-associated genes in primary fibroblast cultures from 30 radiosensitive or radioresistant patients, and found that cells from sensitive patients had the greatest upregulation of inflammation genes with less dependence on radiation type (gamma rays or protons) [21] While these studies have focused on gene expression profiles in the target tissue or cell type, there is great interest in the development of profiles to predict radiation toxicity or therapy outcome from a peripheral blood biopsy. While 4 of the studies in Table 1 have made complete data sets available via the publically accessible GEO database, it is quite surprising
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