Abstract
Hypofractionation is currently considered a valid alternative to conventional radiotherapy for the treatment of patients with organ-confined prostate cancer. Recent data have demonstrated that extreme hypofractionation, which involves the use of a high radiation dose per delivered fraction and concomitant reduction of sessions, is a safe and effective treatment, even though its radiobiological rationale is still lacking. The present work aims to investigate the biological basis sustaining this approach and to evaluate the potential of a hypofractionated regimen in combination with androgen deprivation therapy, one of the major standards of care for prostate cancer. Findings show that androgen receptor (AR) modulation, by use of androgens and antiandrogens, has a significant impact on cell survival, especially in hypoxic conditions (4% O2). Subsequent experiments have revealed that AR activity as a transcription factor is involved in the onset of malignant senescence-associated secretory phenotype (SASP) and activation of DNA repair cascade. In particular, we found that AR stimulation in hypoxic conditions promotes the enhanced transcription of ATM gene, the cornerstone kinase of the DNA damage repair genes. Together, these data provide new potential insights to justify the use of androgen deprivation therapy, in particular with second-generation anti-androgens such as enzalutamide, in combination with radiotherapy.
Highlights
Prostate cancer (PCa) is the second most commonly diagnosed cancer in males, accounting for 7.1% of cancer worldwide [1]
In LNCaP R-bic, a cell line obtained from LNCaP by continuous exposure to 20 μM R-bicalutamide, androgen receptor (AR) maintained a homogeneous expression between normoxia and hypoxia
The PC3 cell line showed no expression of AR and prostate specific antigen (PSA), proving an excellent model of AR-negative PCa
Summary
Prostate cancer (PCa) is the second most commonly diagnosed cancer in males, accounting for 7.1% of cancer worldwide [1]. With regard to PCa management, radiotherapy is one of the most important treatment options and the use of a hypofractionated regimen is currently becoming an area of interest, because of its intrinsic characteristics. E-HFRT is potentially comparable to the high-dose rate of a brachytherapy approach, with the advantage of being less invasive and more economically convenient [6]. Several Phase I and II trials focusing on e-HFRT have recently focused on the management of low and intermediate PCa, with excellent results in terms of short-term toxicity and long-term biochemical control [7,8]. Important Phase III clinical trials are still ongoing or have given recent results, comparing the use of moderate and extreme hypofractionation. Late toxicity and biochemical control results will be released within 2–3 years
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