title: Turning on the Radio: Epigenetic Inhibitors as Potential Radiopriming Agents.
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.
authors.affiliation: EpicentRx, Inc, Mountain View, CA 94040, USA. boronsky@epicentrx.com.
authors.forename: Bryan
authors.initials: B
authors.lastname: Oronsky
authors.affiliation: EpicentRx, Inc, Mountain View, CA 94040, USA. jscicinski@epicentrx.com.
authors.forename: Jan
authors.initials: J
authors.lastname: Scicinski
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, MI 48109, USA. michekim@med.umich.edu.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kim
authors.affiliation: Department of Bioengineering UCSD, La Jolla, San Diego, CA 92093, USA. pcabrales@ucsd.edu.
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.affiliation: KU Medical Center, Kansas University, Kansas City, KS 66160, USA. msalacz@kumc.edu.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Salacz
authors.affiliation: Murtha Cancer Center, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA. corey.carter33@gmail.com.
authors.forename: Corey A
authors.initials: CA
authors.lastname: Carter
authors.affiliation: CFLS Data, Mountain View, CA 94040, USA. nco@cflsdata.com.
authors.forename: Neil
authors.initials: N
authors.lastname: Oronsky
authors.affiliation: Department of Physiology, Helsinki University, 00100 Helsinki, Finland. harrylybeck@gmail.com.
authors.forename: Harry
authors.initials: H
authors.lastname: Lybeck
authors.affiliation: EpicentRx, Inc, Mountain View, CA 94040, USA. lybeck.michelle@gmail.com.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lybeck
authors.affiliation: Moores Cancer Center, UCSD, La Jolla, CA 92093, USA. chris.larson.mail@gmail.com.
authors.forename: Christopher
authors.initials: C
authors.lastname: Larson
authors.affiliation: Moores Cancer Center, UCSD, La Jolla, CA 92093, USA. tonyreid@ucsd.edu.
authors.forename: Tony R
authors.initials: TR
authors.lastname: Reid
authors.affiliation: InterWest Partners, Menlo Park, CA 94025, USA. AOronsky@interwest.com.
authors.forename: Arnold
authors.initials: A
authors.lastname: Oronsky
mesh_terms: D044127:Epigenesis, Genetic; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000235:genetics*
keywords: DNA methyltransferase inhibition; epigenetic priming; epigenetics; histone deacetylase inhibition; radiosensitization; radiotherapy; reactive oxygen species (ROS)