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Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9® to Suppress Enzalutamide-resistant Prostate Cancer Progression.

ABSTRACT: BACKGROUND:While androgen-deprivation-therapy with the recently developed antiandrogen enzalutamide (Enz) shows promising therapeutic benefits in men with metastatic castration-resistant prostate cancer (PCa), many patients develop resistance to Enz, which may involve the induction of the androgen receptor (AR) splicing variant 7 (AR-v7). OBJECTIVE:Our aim is to identify the mechanisms responsible for AR-v7 production and to develop novel preclinical approaches to suppress the Enz-resistant (EnzR) PCa. DESIGN, SETTING, AND PARTICIPANTS:We established EnzR-PCa cell lines and examined the long noncoding RNA Malat1 (Malat1) function in conferring Enz resistance. We also examined the in vivo effects of Malat1 short interfering RNA and the AR-v7 degradation enhancer, ASC-J9®. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Enz resistance and expression of Malat1 and AR-v7. All statistical comparisons were analyzed with a t-test or one way analysis of variance followed by t-test. RESULTS AND LIMITATIONS:We demonstrated that Malat1 is indispensable for Enz-induced AR-v7 production in VCaP and EnzR-C4-2 cells. We observed increased AR-v7 and Malat1 expression in our established EnzR-PCa cell lines and in some PCa patients who received Enz treatment. Targeting the Malat1/AR-v7 axis resulted in altering the PCa resistance to androgen deprivation therapy with Enz. The limitation of this study includes the small sample size from the same human patients before and after receiving Enz treatment. CONCLUSIONS:Targeting the Malat1/AR-v7 axis via Malat1-short interfering RNA or AR-v7 degradation enhancer ASC-J9® in EnzR-PCa cell lines and mouse models suppressed EnzR-PCa progression. PATIENT SUMMARY:Androgen deprivation therapy-enzalutamide treatment may not be the best choice for prostate cancer patients who have higher expression of the Malat1/androgen receptor splicing variant 7 axis, and new therapies using Malat1-short interfering RNA or ASC-J9® may be developed in the future to better suppress enzalutamide-resistant prostate cancer.

SUBMITTER: Wang R

PROVIDER: S-EPMC5802348 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9<sup>®</sup> to Suppress Enzalutamide-resistant Prostate Cancer Progression.

Wang Ronghao R Sun Yin Y Li Lei L Niu Yuanjie Y Lin Wanying W Lin Changyi C Antonarakis Emmanuel S ES Luo Jun J Yeh Shuyuan S Chang Chawnshang C

European urology 20170518 5

<h4>Background</h4>While androgen-deprivation-therapy with the recently developed antiandrogen enzalutamide (Enz) shows promising therapeutic benefits in men with metastatic castration-resistant prostate cancer (PCa), many patients develop resistance to Enz, which may involve the induction of the androgen receptor (AR) splicing variant 7 (AR-v7).<h4>Objective</h4>Our aim is to identify the mechanisms responsible for AR-v7 production and to develop novel preclinical approaches to suppress the Enz ...[more]

PMID: 28528814

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Project description:The androgen receptor (AR) is widely expressed in breast cancers and has been proposed as a therapeutic target in estrogen receptor alpha (ER) negative breast cancers that retain AR. However, controversy exists regarding the role of AR, particularly in ER?+?tumors. Enzalutamide, an AR inhibitor that impairs nuclear localization of AR, was used to elucidate the role of AR in preclinical models of ER positive and negative breast cancer.We examined nuclear AR to ER protein ratios in primary breast cancers in relation to response to endocrine therapy. The effects of AR inhibition with enzalutamide were examined in vitro and in preclinical models of ER positive and negative breast cancer that express AR.In a cohort of 192 women with ER?+?breast cancers, a high ratio of AR:ER (?2.0) indicated an over four fold increased risk for failure while on tamoxifen (HR?=?4.43). The AR:ER ratio had an independent effect on risk for failure above ER % staining alone. AR:ER ratio is also an independent predictor of disease-free survival (HR?=?4.04, 95% CI: 1.68, 9.69; p?=?0.002) and disease specific survival (HR?=?2.75, 95% CI: 1.11, 6.86; p?=?0.03). Both enzalutamide and bicalutamide inhibited 5-alpha-dihydrotestosterone (DHT)-mediated proliferation of breast cancer lines in vitro; however, enzalutamide uniquely inhibited estradiol (E2)-mediated proliferation of ER+/AR?+?breast cancer cells. In MCF7 xenografts (ER+/AR+) enzalutamide inhibited E2-driven tumor growth as effectively as tamoxifen by decreasing proliferation. Enzalutamide also inhibited DHT- driven tumor growth in both ER positive (MCF7) and negative (MDA-MB-453) xenografts, but did so by increasing apoptosis.AR to ER ratio may influence breast cancer response to traditional endocrine therapy. Enzalutamide elicits different effects on E2-mediated breast cancer cell proliferation than bicalutamide. This preclinical study supports the initiation of clinical studies evaluating enzalutamide for treatment of AR+ tumors regardless of ER status, since it blocks both androgen- and estrogen- mediated tumor growth.

Dataset Information

Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9® to Suppress Enzalutamide-resistant Prostate Cancer Progression.

Publications

Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9<sup>®</sup> to Suppress Enzalutamide-resistant Prostate Cancer Progression.

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