Tissue markers may be helpful in enhancing prediction of radiation therapy (RT) failure of prostate cancer (PCa). Among the various biomarkers tested in Phase III randomized trials conducted by the Radiation Therapy Oncology Group, p16, Ki-67, MDM2, COX-2, and PKA yielded the most robust data in predicting RT failure. Other pathways involved in RT failure are also implicated in the development of castration-resistant PCa, including the hypersensitive androgen receptor, EGFR, VEGF-R, and PI3K/Akt. Most of them are detectable in PCa tissue even at the time of initial diagnosis. Emerging evidence suggests that RT failure of PCa results from a multifactorial and heterogeneous disease process. A number of tissue markers are available to identify patients at high risk to fail RT. Some of these markers have the promise to be targeted by drugs currently available to enhance the efficacy of RT and delay disease progression. 1. Introduction Radiation therapy (RT), including brachytherapy, external beam radiation, and proton therapy, is one of the most popular treatment options for clinically localized prostate cancer. A major problem with external beam radiation of solid tumors is the limited amount of radiation which can be safely delivered to the target organ. For prostate cancer, radiation doses are generally limited to <80 Gray because of the increased risk of toxicity at higher doses and the lack of clinical evidence that doses >80 Gray improve local tumor control. New strategies aim to sensitize tumors to radiation [1]. Androgen deprivation therapy (ADT) in combination with RT has been so far the only successful sensitizing strategy that has improved cause-specific survival in men with locally advanced prostate cancer [2, 3]. Various genetic and epigenetic abnormalities have been associated with radiation-resistant PCa (RRPCa). The Radiation Therapy Oncology Group (RTOG) can be credited with having performed the most extensive studies of biomarkers in men with clinically localized prostate cancer treated with external beam radiotherapy on two phase III randomized trials, RTOG 8610 and RTOG 9202. To date, preliminary assessments of p53, DNA ploidy, p16/pRB, Ki-67, MDM2, bcl-2/bax, and CAG repeats, COX-2, Stat3, Cyp3A4, and protein kinase A (PKA) have been completed [4]. It is noteworthy that most of these tissue markers are not specific for RT failure and may have also prognostic implications in PCa patients treated with surgery and androgen deprivation. The present review is focused on pathways implicated in RT failure of PCa to define etiological factors
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