Abstract
First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity.
Highlights
The that this this specific specific hypothesis hypothesisrequires requirestesting testingand andvalidation validationininprospective prospectivetrials, trials, assumption that thethe assumption is is that epigenetic agents will reverse radioresistance based on preliminary evidence of clinical that epigenetic agents will reverse radioresistance based on preliminary evidence of clinical benefit benefit in patients refractory to chemotherapy and immunotherapy
These epigenetic alterations serve as a mechanism for the cancer cell to turn off the transcription of genes that mediate susceptibility and therapy response
Radioresistance is insidious because it is currently impossible a priori to predict tumor response, and radiotherapy carries with it the risk of acute as well as chronic toxicities which may manifest months or even years later [68]
Summary
Radiation therapy (RT) is one of the most frequently used therapeutic modalities with approximately 60% of all cancer patients receiving it in the course of treatment, even though more prescription in the early to. Given the reversibility epigenetic marks, which dynamically regulate gene expression, the nascent issue with chemo‐ andofimmune‐therapies as a means of priming malignant cells to respond Has emerged to address the treatment-resistance issue with chemoand re‐respond) to treatment with epigenetic inhibitors; by extension, the rationale for an episensitization immune-therapies as a means of to priming malignant cells to respond treatment strategy in radiotherapy distilled a simple clinical syllogism (à la all (or menre-respond) are mortal. Socrates to radioresistance unlike genetic(àmutations, epigenetic alterations are reversible ergo, is mortal), is that (1).
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