PO.ET05.03 · 实验与分子治疗
用capivasertib抑制AKT可对抗肿瘤微环境重塑并增强PTEN缺陷型前列腺癌的AR靶向治疗
AKT inhibition with capivasertib counteracts tumor microenvironment remodeling and enhances AR-targeted therapy in PTEN-deficient prostate cancer
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摘要 Abstract
中文摘要
背景：前列腺癌中PTEN缺失激活PI3K/AKT/mTOR信号，驱动广泛的肿瘤微环境（TME）重塑，其特征为间质促纤维增生、血管生成和免疫抑制。Capivasertib（AZD5363），一种强效的泛AKT抑制剂，在与雄激素剥夺疗法（ADT）和abiraterone联合应用时对PTEN缺陷型肿瘤显示出治疗获益，这已在临床前研究和III期CAPItello-281试验中得到证明。
目的：研究AKT抑制如何在AR靶向治疗后调节PTEN缺陷型前列腺癌中的TME失调。
方法：条件性Pten敲除小鼠肿瘤接受基线转录组学分析，以表征AKT驱动的变化和ADT效应。在条件性Pten/Trp53敲除小鼠中，经四周ADT和abiraterone（Abi）治疗（联合或不联合capivasertib）后评估TME应答。分析包括qRT-PCR面板、流式细胞术和定量免疫组织化学（IHC）。
结果：PTEN缺失诱导AKT过度激活，并上调与TME重塑相关的MSigDB标志通路，包括缺氧、血管生成、炎症反应、IL6-STAT3和TGFbeta信号。ADT放大了这些变化，而abiraterone进一步增加了细胞外基质（ECM）重塑基因的表达。Capivasertib联合治疗显著下调了ECM和血管生成相关基因。组织学评估显示，capivasertib治疗的肿瘤中致密、杂乱的胶原沉积减少，炎性浸润减少。IHC证实间质p-S6和p-PRAS40降低，Ki67阳性间质细胞计数降低，以及微血管密度（CD31）降低。PMN细胞、MDSC和TAM（ECM重塑的关键介导者）的基因签名减弱，尤其是在对capivasertib表现出强烈抗肿瘤应答的小鼠中。流式细胞术和IHC证实治疗肿瘤中PMN/MDSC群体的减少。
结论：Capivasertib增强了ADT加abiraterone所实现的肿瘤生长抑制，并减轻了与PTEN缺失和AR靶向治疗相关的TME重塑。这些发现凸显AKT抑制作为对抗TME驱动的疾病进展并改善治疗结局的一种策略。
查看英文原文 English abstract
Background: PTEN loss in prostate cancer activates PI3K/AKT/mTOR signaling, driving extensive tumor microenvironment (TME) remodeling characterized by stromal desmoplasia, angiogenesis, and immune suppression. Capivasertib (AZD5363), a potent pan-AKT inhibitor, has shown therapeutic benefit in PTEN-deficient tumors when combined with androgen deprivation therapy (ADT) and abiraterone, as demonstrated in preclinical studies and the Phase III CAPItello-281 trial.
Objective: To investigate how AKT inhibition modulates TME dysregulation in PTEN-deficient prostate cancer following AR-targeted therapy.
Methods: Conditional Pten-knockout mouse tumors underwent baseline transcriptomic profiling to characterize AKT-driven changes and ADT effects. TME responses were evaluated in conditional Pten/Trp53 knockout mice after four weeks of ADT and abiraterone (Abi), with or without capivasertib. Analyses included qRT-PCR panels, flow cytometry, and quantitative immunohistochemistry (IHC).
Results: PTEN deletion induced AKT hyperactivation and upregulated MSigDB hallmark pathways associated with TME remodeling, including hypoxia, angiogenesis, inflammatory response, IL6-STAT3, and TGFbeta signaling. ADT amplified these changes, while abiraterone further increased extracellular matrix (ECM) remodeling gene expression. Capivasertib co-treatment significantly downregulated ECM and angiogenesis-related genes. Histological evaluation revealed reduced dense, haphazard collagen deposition and fewer inflammatory infiltrates in capivasertib-treated tumors. IHC confirmed decreased stromal p-S6 and p-PRAS40, lower Ki67-positive stromal cell counts, and reduced microvessel density (CD31). Gene signatures for PMN cells, MDSCs, and TAMs-key mediators of ECM remodeling-were diminished, particularly in mice showing strong antitumor responses to capivasertib. Flow cytometry and IHC corroborated the reduction of PMN/MDSC populations in treated tumors.
Conclusion: Capivasertib enhances tumor growth inhibition achieved by ADT plus abiraterone and mitigates TME remodeling associated with PTEN loss and AR-targeted therapy. These findings highlight AKT inhibition as a strategy to counteract TME-driven disease progression and improve therapeutic outcomes.
利益披露 Disclosure
M. A. De Velasco,
AstraZeneca ).
K. Sakai, None..
D. Nakatsu, None..
M. Hashimoto, None..
S. Fujimoto, None..
S. Toyoda, None..
T. Minami, None..
K. Yoshimura, None.
S. T. Barry,
AstraZeneca Employment.
C. Eberlein,
AstraZeneca Employment.
C. Rooney,
AstraZeneca Employment.
K. Nishio,
Nippon Boehringer Ingelheim ).
Eli Lilly Japan ).
Otsuka Pharmaceutica ).
H. Uemura,
AstraZeneca ), Other, Honoraria.
K. Fujita,
Bristol Myers Squibb ).
AstraZeneca Other, Honoraria.
Merck Sharp & Dohme ).
Ono ).