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.

摘要 雄激素受体(AR)及其变异体，如AR-V7的持续表达，尽管AR靶向治疗 有助于晚期CRPC患者的治疗耐药和癌症进展。这突出了 需要新的策略来阻止持续的AR信号。醛酮还原酶家族1成员C3(AKR1C3) 是雄激素合成代谢过程中最重要的基因之一。该酶的活性 不能被阿比特龙抑制。AR/AR-V7和AKR1C3在肿瘤进展和 对目前的治疗方法产生抵抗力。因此，抑制AR/AR-V7和AKR1C3将是理想的 晚期前列腺癌(PCA)的治疗策略。我们设计了一种新的战略来同时 瞄准AR/AR-V7和AKR1C3通路。我们设计并合成了一个新的DUAL文库 根据基于结构的计算机模拟，AKR1C3/AR/AR-变体抑制剂，称为LX。LX的 化合物LX-1在减少细胞数、AR/AR变异体表达和AKR1C3方面的作用最大 活动。RNA-seq分析显示AR和AR-V7信号基因的表达显著降低 通过选定的LX。LX-1抑制睾酮前体雄烯二酮向睾酮的转化 在体外高水平表达AKR1C3的肿瘤细胞中，AKR1C3的表达呈剂量依赖性。此外， LX-1抑制VCaP和LuCaP35CR PDX体内移植瘤生长 肿瘤内的睾丸激素。基于这些发现，总体假设是同时抑制 使用新型LX双重抑制剂的AR/AR突变体和AKR1C3抑制CRPC肿瘤生长，克服 对苯扎鲁胺/阿比特龙的耐药性和改善治疗反应。这个项目是为了进一步 通过了解LX的作用机制(MOA)、测定其疗效、药代动力学来表征LX 和毒性，并确定它们对抗雄激素治疗敏感性的影响，目的是将 以期在今后的临床发展中治疗晚期前列腺癌。我们希望拟议研究的完成将 导致一类新的治疗药物的开发，这些药物针对的是内分泌雄激素的合成 和AR信号。