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Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation.

ABSTRACT: PURPOSEThe current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen-deprived prostate cancer cells leads to formation of double-strand breaks (DSB). Here, we exploit this finding and investigate the extent and timing of androgen-induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR).EXPERIMENTAL DESIGNAndrogen-induced DNA damage was assessed by comet assays and ?H2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models.RESULTSWe document that androgen treatment of androgen-deprived prostate cancer cell lines resulted in a dose- and time-dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor and topoisomerase II beta but not on cell-cycle progression. In vitro models demonstrated a synergistic interaction between IR and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice.CONCLUSIONSThese results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy. Clin Cancer Res; 22(13); 3310-9. ©2016 AACRSee related commentary by Chua and Bristow, p. 3124.

SUBMITTER: Hedayati M

PROVIDER: S-EPMC4930695 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation.

Hedayati Mohammad M Haffner Michael C MC Coulter Jonathan B JB Raval Raju R RR Zhang Yonggang Y Zhou Haoming H Mian Omar O Knight Emma J EJ Razavi Nina N Dalrymple Susan S Isaacs John T JT Santos Aileen A Hales Russell R Nelson William G WG Yegnasubramanian Srinivasan S DeWeese Theodore L TL

Clinical cancer research : an official journal of the American Association for Cancer Research 20160201 13

<h4>Purpose</h4>The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen-deprived prostate cancer cells leads to formation of double-strand breaks (DSB). Here, we exploit this finding and investigate the extent and timing of androgen-induced DSBs an ...[more]

PMID: 26831716

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Project description:ImportanceLong-term control of node-positive (N1) prostate cancer, the incidence of which is increasing, is obtainable with aggressive treatment, and definitive external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT) is an increasingly preferred option. Caring for these patients is complex and may require resources more readily available at high-volume centers.ObjectiveTo evaluate the association between radiation facility case volume and overall survival (OS) in men with N1 prostate cancer.Design, setting, and participantsThis cohort study included 1899 men diagnosed with T1N1M0 to T4N1M0 prostate cancer treated with curative-intent EBRT and ADT between January 2004 and December 2016 at US facilities reporting to the National Cancer Database. Data analysis was performed from March to June 2020.ExposuresTreatment at a center with high vs low average cumulative facility volume (ACFV), defined as the total number of prostate radiation cases at an individual patient's treatment facility from 2004 until the year of that patient's diagnosis.Main outcomes and measuresOS was assessed between high- vs low-ACFV centers using the Kaplan-Meier method with and without propensity score-based weighted adjustment and multivariable Cox proportional hazards. The nonlinear association between continuous ACFV and OS was examined through a Martingale residual plot, and the optimal ACFV cutoff point that maximized the separation between high vs low ACFV was identified via a bias adjusted log rank test.ResultsA total of 1899 men met inclusion criteria. The median (interquartile range) age was 66 (60-72) years, 1491 (78.5%) were White individuals, and 1145 (60.3%) were treated at nonacademic centers. The optimal ACFV cutoff point was 66.4 patients treated per year. The median OS for patients treated at high-ACFV vs low-ACFV centers was 111.1 (95% CI, 101.5-127.9) months and 92.3 (95% CI, 87.7-103.9) months, respectively (P = .01). On multivariable analysis, treatment at a low-ACFV center was associated with increased risk of death (HR, 1.22; 95% CI, 1.02-1.46, P = .03) compared with treatment at a high-ACFV center. These results persisted after propensity score-based adjustment.Conclusions and relevanceThis cohort study found a significant association of facility case volume with long-term outcomes in men with N1 prostate cancer undergoing EBRT with ADT. Specifically, treatment at a facility with high radiation case volume was independently associated with longer OS. Further studies should focus on identifying which factors unique to high-volume centers may be responsible for this benefit.

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Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation.

Publications

Androgen Deprivation Followed by Acute Androgen Stimulation Selectively Sensitizes AR-Positive Prostate Cancer Cells to Ionizing Radiation.

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