Novel therapeutics dual targeting intracrine androgen synthesis and AR for advanced prostate cancer

双靶向内分泌雄激素合成和 AR 治疗晚期前列腺癌的新型疗法

• 批准号: 10808574
• 负责人: Allen C Gao
• 金额: $ 7.36万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10808574
• 关键词: Androgen Antagonists; Androgen Receptor; Androgens; Androstenedione; Antiandrogen Therapy; Automobile Driving; Cell Count; Computer Models; Development; Dose; Drug Kinetics; Family; Future; Genes; Goals; Libraries; Metabolism; Oxidoreductase; Pathway interactions; Patients; Play; Receptor Signaling; Resistance; Role; Safety; Signal Transduction; Structure; Testosterone; Toxic effect; Translating; VCaP; Variant; Xenograft procedure; abiraterone; advanced prostate cancer; clinical development; design; efficacy evaluation; enzalutamide; enzyme activity; improved; in vivo; inhibitor; member; neoplastic cell; novel; novel strategies; novel therapeutics; prostate cancer progression; small molecule; targeted treatment; therapy resistant; transcriptome sequencing; treatment response; tumor growth; tumor progression

ABSTRACT Continued expression of androgen receptor (AR) and its variants, such as AR-V7, despite AR targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the need for new strategies to block continued AR signaling. Aldo-keto reductase family 1 member C3 (AKR1C3) is one of the most important genes involved in androgen synthesis and metabolism. Activity of this enzyme cannot be inhibited by abiraterone. Both AR/AR-V7 and AKR1C3 play key roles in cancer progression and driving resistance to current therapies. Therefore, inhibition of both AR/AR-V7 and AKR1C3 would be an ideal strategy for treating advanced prostate cancer (PCa). We have designed a novel strategy to simultaneously target the AR/AR-V7 and AKR1C3 pathways. We designed and synthesized a library of novel dual AKR1C3/AR/AR-variant inhibitors, called LX, according to structure-based computer modeling. Of the LX compounds, LX-1 had the greatest effect at reducing cell number, AR/AR variant expression, and AKR1C3 activity. RNA-seq analysis demonstrated a robust reduction in expression of AR and AR-V7 signaling genes by the selected LX. LX-1 inhibited conversion of the testosterone precursor androstenedione into testosterone in tumor cells which express high levels of AKR1C3 in a dose-dependent manner ex vivo. Furthermore, treatment with LX-1 reduced tumor growth in VCaP and LuCaP35CR PDX xenografts in vivo and decreased intratumoral testosterone. Based on these findings, the overall hypothesis is that concurrent inhibition of AR/AR variants and AKR1C3 using novel LX dual inhibitor suppresses CRPC tumor growth, overcomes resistance and improves treatment response to enzalutamide/abiraterone. This project is to further characterize LX by understanding its mechanism of action (MOA), determining its efficacy, pharmacokinetics and toxicity, and to determine their effects on the sensitivity to anti-androgen therapy with the goal to translate to future clinical development to treat advanced PCa. We hope that completion of the proposed studies will lead to the development of a new class of therapeutic agents that target both intracrine androgen synthesis and the AR signaling.

抽象的 尽管AR靶向治疗 在晚期CRPC患者中有助于治疗耐药性和癌症进展。这突出了 需要新的策略来阻止持续的AR信号传导。 Aldo-Keto还原酶家族1成员C3（AKR1C3） 是参与雄激素合成和代谢的最重要基因之一。该酶的活性 不能被阿比罗酮抑制。 AR/AR-V7和AKR1C3都在癌症进展和 驱动对当前疗法的抗药性。因此，抑制AR/AR-V7和AKR1C3将是理想的 治疗晚期前列腺癌（PCA）的策略。我们设计了一种新颖的策略来同时 靶向AR/AR-V7和AKR1C3途径。我们设计和合成了一个新颖的双重库 根据基于结构的计算机建模，AKR1C3/AR/AR-VARIANT抑制剂称为LX。 lx 化合物LX-1在降低细胞数，AR/AR变体表达和AKR1C3方面具有最大的作用 活动。 RNA-seq分析表明AR和AR-V7信号基因的表达有强大的降低 由选定的LX。 LX-1抑制了睾丸激素前体雄激素转化为睾丸激素 在肿瘤细胞中，以剂量依赖性方式表达高水平的AKR1C3。此外， 用LX-1治疗VCAP和LUCAP35CR PDX异种移植物在体内的肿瘤生长降低并减少 肿瘤内睾丸激素。基于这些发现，总体假设是同时抑制 使用新型LX双重抑制剂抑制CRPC肿瘤生长，AR/AR变体和AKR1C3克服了 耐药并改善了对恩扎拉胺/阿比罗酮的治疗反应。这个项目将进一步 通过了解其作用机理（MOA），确定其功效，药代动力学来表征LX 和毒性，并确定它们对抗雄激素治疗的敏感性的影响，以翻译目标 为了治疗晚期PCA的未来临床开发。我们希望拟议的研究完成 导致开发一种新的靶向雄激素合成的新型治疗剂 和AR信号。