阿比特龙降低前列腺癌对化疗敏感性的作用机制及应对策略的研究

Abiraterone, a new-generation androgen-deprivation complex, exerts its anti-tumour activity through inhibiting intratumoral androgen synthesis and will hopefully be issued by CFDA against castration-resistant prostate cancer (CRPC) in coming days. Docetaxel provides the first-line chemotherapy for prostate cancer patients who failed hormonal therapy. Very recently, it was found that men receiving abiraterone before docetaxel were less likely to achieve comparable response than abiraterone-naïve patients, while the underlying mechanism remains poorly investigated. .Our preliminary data indicate that (1) histone methyltransferase SMYD3 plays critical role in the progression of prostate cancer and its expression could be induced with abiraterone treatment; (2) the abiraterone-induced docetaxel resistance might be reversed by SMYD3 inhibition. Our project aims to (1) explore the mechanism of abiraterone-induced docetaxel cross-resistance；(2) to study the feasibility of reversing abiraterone-induced docetaxel resistance with SMYD3 inhibition. The project promises to provide further mechanistic understanding of abiraterone-induced docetaxel cross-resistance and the potential solution based on SMYD3 inhibition.

新一代前列腺癌激素治疗药物阿比特龙通过降低肿瘤内雄激素水平抑制肿瘤生长，将于近期在我国应用于去势抵抗型前列腺癌（CRPC）。多西他赛是前列腺癌激素治疗失败后的一线化疗药物。最新研究发现在阿比特龙-多西他赛的序贯治疗过程中，阿比特龙会显著降低前列腺癌对多西他赛的敏感性，造成阿比特龙-多西他赛交叉耐药，但具体机制尚无研究报道。.我们初步研究发现：1.组蛋白甲基化酶SMYD3在CRPC发展过程中起到关键作用，其表达水平可被阿比特龙诱导升高；2.通过抑制 SMYD3活性可能逆转阿比特龙诱导的多西他赛的耐药。本项目旨在探讨1.阿比特龙降低CRPC对多西他赛化疗敏感性的作用机制；2.通过抑制SMYD3活性逆转阿比特龙诱导的多西他赛耐药的可行性及机制。本研究将有助于深入了解阿比特龙诱导多西他赛交叉耐药的机制以及阿比特龙耐药型CRPC的分子生物学特性，为逆转阿比特龙诱导的多西他赛耐药提供应对策略。

前列腺癌激素治疗药物阿比特龙通过降低肿瘤内雄激素水平抑制肿瘤生长, 近来广泛应用于去势抵抗型前列腺癌（CRPC）。阿比特龙会显著降低前列腺癌对化疗的敏感性，造成阿比特龙-多西他赛交叉耐药。 本课题探索阿比特龙降低前列腺癌对化疗敏感性的作用机制。我们研究成果主要包括：(1)阐明了阿比特龙耐药患者的基因组学特征及转录学组特征；(2) 发现了阿比特龙诱导前列腺癌细胞对多西他赛耐药的主要肿瘤驱动基因及通路，包括；AR、SMYD3、激酶通路及细胞调控通路。(3) 阐明了SMYD3通过直接激活表皮生长因子受体（EGFR）转录与表达起到维持肿瘤细胞生长的作用及具体作用机制。本研究结果有助于阐明CRPC治疗过程中阿比特龙诱导细胞对多西他赛耐药的机制，并为基于SMYD3抑制剂的治疗提供新思路。