新型硒类化合物对晚期前列腺癌的治疗作用及其分子机制的研究

Prostate cancer has become the 7th most commonly diagnosed cancer among men in China. Due to the lack of effective prostate cancer screening programs in our country, most of the patients are diagnosed at an advanced stage, and androgen deprivation therapy is the mainstay treatment. Current androgen deprivation therapy targets the action of androgen receptor by reducing circulating androgen level through surgical or chemical castration and/or by disrupting the binding of androgens to androgen receptor with anti-androgen. Despite the initial efficacy of androgen deprivation therapy, relapse with incurable and lethal castration-resistant prostate cancer invariably occurs and remains the major challenge in the treatment of advanced prostate cancer. The main mechanism for the development of castration resistance is androgen receptor reactivation. Several new drugs targeting androgen receptor reactivation, such as Abiraterone and MDV3100, are showing considerable promise in treating patients with castration-resistant prostate cancer. However, even with these new drugs, the time to disease progression and overall survival still remain relatively short. One potential mechanism of disease progression is upregulation of androgen receptor and its constitutively-active, ligand-binding-domain-truncated splice variants. Thus, there is an urgent need to develop effective strategies to reduce the availability of both the full-length androgen receptor and its splice variants in order to inhibit prostate cancer recurrence after current and new androgen deprivation therapy. . We showed that two second-generation selenium compounds, methylseleninic acid and methylselenocysteine, can effectively reduce the levels of androgen receptor and its splice variants, significantly enhance the apoptosis-inducing efficacy of anti-androgen in both androgen-dependent and castration-resistant prostate cancer cells, and inhibit prostate tumor relapse after castration in a xenograft model. The objective of this application is to conduct both in vitro and in vivo studies to determine the efficacy of these second-generation selenium compounds in improving the therapeutic outcome of current and new androgen deprivation therapy, and to elucidate the underlying molecular mechanism. The proposed study represents a key step in a continuum of research that is expected to lead to the development of a novel therapeutic modality that will considerably improve the outcome of androgen deprivation therapy. Since the development of resistance to androgen deprivation therapy constitutes the major cause of prostate cancer mortality, the research is expected to contribute to a significant reduction in prostate-cancer death rate. Additionally, elucidating the mechanism mediating the action of these selenium compounds is fundamental for the development of a tailored therapeutic strategy in selecting patients for intervention.

在我国，前列腺癌发病率在男性恶性肿瘤中已居第七位。大部分患者就诊时病情已经达到晚期，因此雄激素剥夺疗法是主要疗法。该疗法治疗后的病情复发，并发展成去势难治性是晚期前列腺癌治疗迫切需要解决的问题。近年来，欧美国家研制出了阿比特龙和MDV3100等新一代雄激素剥夺药物，但这些新药仅能使患者存活期延长4-5个月。研究表明，雄激素受体及其剪切变异体高表达是前列腺癌对传统和新一代雄激素剥夺疗法产生抗性的主要机制。我们前期研究表明新型硒类化合物甲基硒酸和甲基硒代半胱氨酸可有效地降低雄激素受体及其变异体的表达，提高传统雄激素剥夺疗法的体外疗效，并抑制耐药性的形成，提示其在晚期前列腺癌治疗中的潜在价值。本项目拟深入地探讨这两种硒类化合物在晚期前列腺癌治疗中的作用，通过体内外实验系统验证其对传统和新一代雄激素剥夺疗法的辅助作用，同时从分子水平阐明其作用机制，为其应用于晚期前列腺癌的治疗提供更坚实的理论基础。

雄激素剥夺法治疗后的前列腺癌的复发，并发展成去势难治性是晚期前列腺癌治疗迫切需要解决的问题。 研究表明，全长的雄激素受体（AR-FL）及其剪切变异体（AR-V）的高表达是前列腺癌对传统和新一代雄激素剥夺疗法 MDV3100产生抗性的主要机制。我们前期研究表明新型硒类化合物甲基硒酸（MSA）和甲基硒代半胱氨酸（MSC）可有效地降低AR-FL和AR-V的表达，提高传统雄激素剥夺疗法的体外疗效，并抑制耐药性的形成，提示其在晚期前列腺癌治疗中的潜在价值。本项目拟深入地探讨这两种硒类化合物在晚期前列腺癌治疗中的作用，通过体内外实验系统验证其对传统和新一代雄激素剥夺疗法的辅助作用，同时从分子水平阐明其作用机制，为其应用于晚期前列腺癌的治疗提供更坚实的理论基础。.在基金资助期间，我们完成了以下工作：.第一，我们发现MSA能够增强MDV3100对AR活性的抑制作用，还可增强MDV3100的抗癌活性，并阐明了其分子机理。 这些实验结果表明MSA可有效地提高MDV3100在晚期前列腺癌治疗中的疗效 。.第二，我们发现MSC能够延缓去势后前列腺癌移植瘤向去势难治性转化的进程，并阐明了其分子机理。 这些实验结果表明MSC可有效地提高传统雄激素剥夺疗法在晚期前列腺癌治疗中的疗效 。.第三，我们发现人参皂甙20(S)-原人参二醇（PPD）有与新型硒类化合物同样的活性，能够有效地降低AR-FL和AR-V的表达，并延缓去势后前列腺癌移植瘤向去势难治性转化的进程。这些实验结果拓展了我们的研究范围，表明PPD与新型硒类化合物均可有效地提高传统雄激素剥夺疗法在晚期前列腺癌治疗中的疗效 。.第四，我们发现定位于包质中的AR-V：AR-V7和ARv567es可以与AR-FL形成异源二聚体，诱导AR-FL的核转移，激活典型AR靶基因的表达，还可以同源二聚体的方式诱导其特异靶基因的表达。我们还发现主要定位于包浆中的AR-Vs可以通过与AR-V7及AR-FL形成异源二聚体进入细胞质内来行使转录功能并促进前列腺癌细胞去势难治性生长。这些实验结果为研发AR-V抑制剂，从而更有效地抑制去势难治性前列腺癌的发生和发展提供坚实的理论基础 。