Targeting AR variants in advanced prostate cancer

尽管Enzalutamide和阿比特龙最初对去势抵抗性前列腺增生的治疗有效， 在癌症（CRPC）中，对这两种药物的耐药性经常通过不完全的机制发生， 明白大量的临床和实验研究证据表明，雄激素 受体剪接变体AR-V7在促进CRPC进展和诱导对CRPC的耐药性方面起着重要作用。 恩杂鲁胺和阿比特龙AR-V7不被恩杂鲁胺或阿比特龙靶向，因此， 迫切需要开发靶向AR-V7以克服耐药性的新治疗策略。 目前，尽管有令人信服的实验结果，但没有AR-V7靶向剂显示出对CRPC的临床疗效。 以及支持AR-V7在耐药CRPC中的明确作用的临床数据。我们之前发现， 氯硝柳胺是FDA批准用于治疗绦虫感染的驱虫剂， 表达AR变体如AR-V7，并克服对恩杂鲁胺和阿比特龙的抗性。 临床前CRPC模型。为了提高氯硝柳胺的生物利用度和药效，我们合成了一个库 氯硝柳胺类似物根据预测的生物利用度。我们已经鉴定了几种新的小分子 AR-V7抑制剂（ARVib）。我们发现，ARVib在抑制AR-V7表达方面具有更好的功效， V7介导的转录活性，和抗CRPC肿瘤生长比氯硝柳胺。而且我们 证明ARVib与恩杂鲁胺/阿比特龙协同作用。该提案旨在从功能上 表征和验证最有前途的AR变体抑制剂（ARVib），并开发下一代 通过使用ARVib靶向AR-V7治疗耐药CRPC的治疗策略。总的假设是， ARVib抑制AR变体可抑制CRPC肿瘤生长并克服对改善CRPC的耐药性。 Enzalutamide/阿比特龙治疗。在目标1和2中，我们将表征和优化所确定的选择性 AR变体的抑制剂（ARVib），并评估这些ARVib的抗肿瘤活性及其 耐药CRPC和PDX模型中耐药细胞对Enzalutamide/阿比特龙治疗敏感的能力， 体外和体内。目的3将确定ARVib在抗肿瘤活性中的作用机制（MOA）， 对Enzalutamide/阿比特龙再敏感。

Although enzalutamide and abiraterone are effective initially for the treatment of castration-resistant prostate cancer (CRPC), resistance to both drugs occurs frequently through the mechanisms which are incompletely understood. Considerable evidence from both clinical and experimental studies demonstrated that androgen receptor splice variant AR-V7 plays vital roles in promoting CRPC progression and induction of resistance to enzalutamide and abiraterone. AR-V7 is not targeted by either enzalutamide or abiraterone and therefore, there is an urgent need to develop novel treatment strategies that target AR-V7 to overcome resistance. Currently, no AR-V7 targeting agents have shown clinical efficacy for CRPC despite convincing experimental and clinical data supporting a clear role for AR-V7 in resistant CRPC. We previously identified that niclosamide, an anthelmintic agent approved by the FDA for the treatment of tapeworm infections, inhibits expression of AR variants such as AR-V7 and overcomes resistance to enzalutamide and abiraterone in preclinical CRPC models. To improve the bioavailability and potency of niclosamide, we synthesized a library of niclosamide analogs according to predicted bioavailability. We have identified several novel small molecule inhibitors of AR-V7 (ARVib). We showed that ARVib has better efficacy in inhibition of AR-V7 expression, AR- V7 mediated transcriptional activity, and anti-CRPC tumor growth than niclosamide. Furthermore, we demonstrated that ARVib synergizes with enzalutamide/abiraterone. This proposal is aimed to functionally characterize and validate the most promising AR variant inhibitors (ARVib) and develop next generation treatment strategies for resistant CRPC by targeting AR-V7 using ARVib. The overall hypothesis is that inhibition of AR variants by ARVib suppresses CRPC tumor growth and overcomes resistance to improve enzalutamide/abiraterone therapy. In Aims 1 and 2, we will characterize and optimize the identified selective inhibitors of AR variants (ARVib), and evaluate the efficacy of these ARVib for their anti-tumor activity and their ability to sensitize resistant cells to enzalutamide/abiraterone treatment in resistant CRPC and PDX models in vitro and in vivo. Aim 3 will determine the mechanisms of action (MOA) of the ARVib in anti-tumor activity and resensitization to enzalutamide/abiraterone.