Targeting intracrine steroidogenesis in anti-androgen resistant prostate cancer

项目摘要 前列腺癌（PCa）是2022年美国男性癌症相关死亡的第二大原因。 有限数量的PCa细胞系和患者来源的异种移植物（PDX）模型阻碍了改善PCa细胞增殖的研究。 疾病结果。为了满足这一未满足的需求，我们开发了多种PDX模型， 重编程培养物（CRC）和晚期疾病患者的类器官。AKR1C3，也被称为 HSD17B5是参与雄激素代谢的最重要的基因之一，其表达升高， 这种酶与前列腺癌进展和雄激素受体途径抑制剂（ARPI）治疗失败有关 治疗。我们已经报道了AKR1C3的上调，同时伴随着睾酮水平的升高， 前列腺癌细胞和异种移植肿瘤中对抗雄激素治疗有抗性的前体。这 一项提案将使用血液AKR1C3和血浆类固醇水平作为生物标志物， ARPI治疗的患者中类固醇生成激活表示耐药性。我们还将测试一本小说 在新建立的PDX和CRC模型中使用AKR1C3抑制剂。该抑制剂具有很大的潜力， ARPI治疗晚期PCa的有效性，这可能直接转化为临床试验。的目标 该项目旨在鉴定新的生物标志物并开发新的药物方法， 用ARPI靶向新辅助治疗CRPC患者。操纵关键酶有助于 雄激素的产生潜在地为晚期前列腺癌的治疗提供了一种新的靶向疗法， 这将对病人的生活产生有意义的影响。从该项目获得的数据将建立一个 为患者治疗制定临床相关决策，并为未来的精准医疗铺平道路， 前列腺癌

PROJECT ABSTRACT Prostate cancer (PCa) is the second leading cause of cancer related death in men in the United States in 2022. A limit number of PCa cell lines and patient-derived xenograft (PDX) models hinders research to improve disease outcome. To address this unmet need, we have developed multiple PDX models, conditional reprogramed cultures (CRCs) and organoids from patients with advanced disease. AKR1C3, also named HSD17B5, is one of the most important genes involved in androgen metabolism and elevated expression of this enzyme is associated with PCa progression and failure to androgen receptor pathway inhibitors (ARPIs) treatments. We have reported that upregulation of AKR1C3, concurrent with elevated testosterone and its precursors in prostate cancer cells and xenograft tumors that are resistant to anti-androgen treatments. This proposal will use blood AKR1C3 and plasma steroid levels as biomarkers to interrogate intracrine steroidogenesis activation in ARPIs treated patients to signify drug resistance. We will also test a novel AKR1C3 inhibitor in the newly established PDX and CRC models. The inhibitor has great potential to increase efficacy of ARPIs treatments in advanced PCa which might translate into the clinical trial directly. The goal of this program is to identify novel biomarkers and develop new pharmaceutical approaches to provide co- targeting neoadjuvant with ARPIs to treat CRPC patients. Manipulation of key enzymes contributing to the production of androgen potentially offers a novel targeted therapy for the advanced prostate cancer treatment, which will have a meaningful impact on patients’ lives. The data acquired from this project will establish a clinically relevant decision making for patient treatment and pave the way to future precision medicine in prostate cancer.