Abstract
Simple SummaryThe combination of RT and the first generation AR blockers to improve the outcome in prostate cancer remain a matter of controversial debate in clinical trials. In the current study we aim to investigate the effect of three FDA approved second-generation antiandrogens (abiraterone acetate, apalutamide and enzalutamide), as more potent inhibitors of the AR signaling, on the cytotoxicity of RT in pre-clinical models. In vitro and ex vivo analyses revealed a strong radiosensitising effect for the second-generation antiandrogens, regardless of the castration state. The first-generation AR-blocker bicalutamide failed to show any radiosensitising effect. The radiosensitising effect of the second-generation antiandrogens was attributed to the inhibition of DSB repair. Together, we provide a proof-of-principle pre-clinical evidence to rationalize the clinical use of the second-generation antiandrogens to enhance the effect of IR as a potential strategy to improve the outcomes of PCa patients with localized disease who undergo ablative RT.(1) Background: The combination of the first-generation antiandrogens and radiotherapy (RT) has been studied extensively in the clinical setting of prostate cancer (PCa). Here, we evaluated the potential radiosensitizing effect of the second-generation antiandrogens abiraterone acetate, apalutamide and enzalutamide. (2) Methods: Cell proliferation and agarose-colony forming assay were used to measure the effect on survival. Double strand break repair efficiency was monitored using immunofluorescence staining of γH2AX/53BP1. (3) Results: We report retrospectively a minor benefit for PCa patients received first-generation androgen blockers and RT compared to patients treated with RT alone. Combining either of the second-generation antiandrogens and 2Gy suppressed cell growth and increased doubling time significantly more than 2Gy alone, in both hormone-responsive LNCaP and castration-resistant C4-2B cells. These findings were recapitulated in resistant sub-clones to (i) hormone ablation (LNCaP-abl), (ii) abiraterone acetate (LNCaP-abi), (iii) apalutamide (LNCaP-ARN509), (iv) enzalutamide (C4-2B-ENZA), and in castration-resistant 22-RV1 cells. This radiosensitization effect was not observable using the first-generation antiandrogen bicalutamide. Inhibition of DNA DSB repair was found to contribute to the radiosensitization effect of second-generation antiandrogens, as demonstrated by a significant increase in residual γH2AX and 53BP1 foci numbers at 24h post-IR. DSB repair inhibition was further demonstrated in 22 patient-derived tumor slice cultures treated with abiraterone acetate before ex-vivo irradiation with 2Gy. (4) Conclusion: Together, these data show that second-generation antiandrogens can enhance radiosensitivity in PCa through DSB repair inhibition, regardless of their hormonal status. Translated into clinical practice, our results may help to find additional strategies to improve the effectiveness of RT in localized PCa, paving the way for a clinical trial.
Highlights
Prostate cancer (PCa) remains one of the most frequent cancers, and a leading cause of cancer death [1]
Due to the increasing interest for the use of combined antiandrogenic therapy with radiation therapy (RT) in the management of prostate cancer (PCa), we performed a retrospective analysis, employing a cohort of 166 PCa patients treated with RT with or without androgen deprivation therapy (ADT), between 2008 and 2016 at our institution
For low risk PCa patients treated with ADT plus RT, the Radiation Therapy Oncology Group (RTOG) 94-08 trial failed to show any significant improvement in disease control
Summary
Prostate cancer (PCa) remains one of the most frequent cancers, and a leading cause of cancer death [1]. ADT acts by either inhibiting the testosterone production within the testicular stroma through interfering with luteinizing hormone releasing hormone (LHRH) from the pituitary gland or a direct blockade of androgen binding to the androgen receptor (AR). Both approaches block AR signaling, which is the major driver of PCa growth and progression [2]. Despite the immediate palliative benefits that can be achieved by ADT, the majority of patients relapse within a few years, due to alternative mechanisms of AR signaling, AR amplification or alternative splicing, intratumoral androgen production, or adrenal gland testosterone production. Rising prostate-specific antigen (PSA) values or detectable disease progression despite the appropriate suppression of systemic testosterone levels characterize castration resistance, a major driver of PCa-associated mortality [6,7]
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