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: 10573314
• 负责人: Allen C Gao
• 金额: $ 52.11万
• 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/10573314
• 关键词: ATAC-seq; Androgen Antagonists; Androgen Receptor; Androgens; Androstenedione; Antiandrogen Therapy; Automobile Driving; Biological Availability; CWR22Rv1; Cancer Patient; Castration; Cell Count; Cell Line; Cells; ChIP-seq; Chromatin; Chronic; Clinical; Computer Models; Data; Development; Dose; Drug Kinetics; Drug resistance; Enzymes; Family; Future; Genes; Genomic approach; Goals; Growth; In Vitro; Laboratories; Legal patent; Libraries; Metabolism; Oxidoreductase; Pathway interactions; Patients; Play; Production; Receptor Signaling; Resistance; Role; Safety; Signal Transduction; Structure; Technology; Testing; Testosterone; Toxic effect; Translating; Treatment outcome; VCaP; Variant; Xenograft procedure; abiraterone; advanced prostate cancer; cell growth; clinical development; design; efficacy evaluation; enzalutamide; enzyme activity; functional genomics; genome-wide; improved; in vivo; in vivo Model; inhibitor; member; neoplastic cell; novel; novel strategies; novel therapeutics; patient derived xenograft model; prostate cancer progression; small molecule; targeted treatment; therapy resistant; transcriptome; transcriptome sequencing; treatment response; tumor; tumor growth; tumor microenvironment; 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.

摘要 雄激素受体（AR）及其变体（如AR-V7）持续表达，尽管接受了AR靶向治疗 导致晚期CRPC患者的治疗抵抗和癌症进展。这凸显 需要新的策略来阻断持续的AR信号传导。醛酮还原酶家族1成员C3（AKR 1C 3） 是参与雄激素合成和代谢的最重要的基因之一。该酶活性 不能被阿比特龙抑制。AR/AR-V7和AKR 1C 3在癌症进展中起关键作用， 导致对当前疗法的抵抗。因此，抑制AR/AR-V7和AKR 1C 3两者将是理想的方法。 治疗晚期前列腺癌（PCa）的策略。我们设计了一种新的策略， 靶向AR/AR-V7和AKR 1C 3通路。我们设计并合成了一个新的双 AKR 1C 3/AR/AR变体抑制剂，称为LX，根据基于结构的计算机建模。关于LX LX-1在减少细胞数量、AR/AR变体表达和AKR 1C 3方面具有最大的效果， 活动RNA-seq分析表明AR和AR-V7信号传导基因的表达显著降低 选择LX LX-1抑制睾酮前体雄烯二酮转化为睾酮 在离体以剂量依赖性方式表达高水平AKR 1C 3的肿瘤细胞中。此外，委员会认为， 用LX-1处理减少体内VCaP和LuCaP 35 CR PDX异种移植物中的肿瘤生长，并且减少VCaP和LuCaP 35 CR PDX异种移植物中的肿瘤生长。 瘤内睾酮基于这些发现，总的假设是， 使用新型LX双重抑制剂的AR/AR变体和AKR 1C 3抑制CRPC肿瘤生长，克服 耐药性并改善对enzalutamide/阿比特龙的治疗反应。该项目将进一步 通过了解LX的作用机制（MOA）、确定其疗效、药代动力学 和毒性，并确定其对抗雄激素治疗的敏感性的影响，目的是转化为 用于治疗晚期前列腺癌的未来临床开发。我们希望完成拟议的研究后， 导致开发了一类新的治疗剂，其靶向内分泌雄激素合成 和AR信号。