Targeting AR variants in advanced prostate cancer

虽然苯扎鲁胺和阿比特龙最初对治疗去势抵抗的前列腺有效 癌症(CRPC)，对这两种药物的耐药性经常通过不完全的机制发生 明白了。来自临床和实验研究的大量证据表明，雄激素 受体剪接变异体AR-V7在促进CRPC进展和诱导耐药中发挥重要作用 苯扎鲁胺和阿比特龙。AR-V7不是苯扎鲁胺或阿比特龙的靶标，因此， 迫切需要开发针对AR-V7的新的治疗策略来克服耐药性。 目前，尽管有令人信服的实验，但还没有AR-V7靶向药物显示出对CRPC的临床疗效 临床数据支持AR-V7在耐药CRPC中的明确作用。我们之前发现， 氯硝柳胺是一种被FDA批准用于治疗绦虫感染的驱虫剂，它抑制 AR-V7等AR变异体的表达及克服对苯扎鲁胺和阿比特龙的耐药性 临床前CRPC模型。为了提高氯硝柳胺的生物利用度和有效性，我们合成了一个文库 根据预测的生物利用度计算氯硝柳胺类似物。我们已经确定了几个新的小分子 AR-V7抑制剂(ARVib)。结果表明，ARVib对AR-V7的表达有较好的抑制作用，AR-V7、AR-V7、AR-V7的表达与AR-V7、AR-V7的表达呈正相关。 V7介导的转录活性和抗CRPC肿瘤生长作用优于氯硝柳胺。此外，我们 证明ARVib与苯扎鲁胺/阿比特龙有协同作用。这项提议的目的是在功能上 表征和验证最有前景的AR变异型抑制剂(ARVib)并开发下一代 ARVib靶向AR-V7治疗耐药CRPC的策略总体假设是 ARVib抑制AR变异体抑制CRPC肿瘤生长并克服耐药性改善 苯扎鲁胺/阿比特龙治疗。在目标1和目标2中，我们将描述和优化已确定的选择性 AR变异体抑制物(ARVib)，并评价这些ARVib的抗肿瘤活性和它们的 在耐药的CRPC和PDX模型中使耐药细胞对苯扎鲁胺/阿比特龙治疗增敏的能力 体外和体内。目标3将确定ARVib抗肿瘤活性的作用机制和 对苯扎鲁胺/阿比特龙的复敏作用。

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.