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Leptin antagonism inhibits prostate cancer xenograft growth and progression.
Endocrine-Related Cancer ( IF 4.1 ) Pub Date : 2021-04-29 , DOI: 10.1530/erc-20-0405
Lisa K Philp 1 , Anja Rockstroh 1 , Martin C Sadowski 1 , Atefeh Taherian Fard 1 , Melanie Lehman 1 , Gregor Tevz 1 , Michelle S Libério 1 , Charles L Bidgood 1 , Jennifer H Gunter 1 , Stephen McPherson 1 , Nenad Bartonicek 2 , John D Wade 3, 4 , Laszlo Otvos 5, 6 , Colleen C Nelson 1
Affiliation  

Hyperleptinaemia is a well-established therapeutic side effect of drugs inhibiting the androgen axis in prostate cancer (PCa), including main stay androgen deprivation therapy (ADT) and androgen targeted therapies (ATT). Given significant crossover between the adipokine hormone signalling of leptin and multiple cancer-promoting hallmark pathways, including growth, proliferation, migration, angiogenesis, metabolism and inflammation, targeting the leptin axis is therapeutically appealing, especially in advanced PCa where current therapies fail to be curative. In this study, we uncover leptin as a novel universal target in PCa and are the first to highlight increased intratumoural leptin and leptin receptor (LEPR) expression in PCa cells and patients' tumours exposed to androgen deprivation, as is observed in patients' tumours of metastatic and castrate resistant (CRPC) PCa. We also reveal the world-first preclinical evidence that demonstrates marked efficacy of targeted leptin-signalling blockade, using Allo-aca, a potent, specific, and safe LEPR peptide antagonist. Allo-aca-suppressed tumour growth and delayed progression to CRPC in mice bearing LNCaP xenografts, with reduced tumour vascularity and altered pathways of apoptosis, transcription/translation, and energetics in tumours determined as potential mechanisms underpinning anti-tumour efficacy. We highlight LEPR blockade in combination with androgen axis inhibition represents a promising new therapeutic strategy vital in advanced PCa treatment.

中文翻译:

瘦素拮抗作用抑制前列腺癌异种移植物的生长和进展。

高瘦素血症是一种公认​​的抑制前列腺癌 (PCa) 中雄激素轴的药物的治疗副作用,包括主要的雄激素剥夺疗法 (ADT) 和雄激素靶向疗法 (ATT)。鉴于瘦素的脂肪因子激素信号传导与多种促进癌症的标志性途径(包括生长、增殖、迁移、血管生成、代谢和炎症)之间存在显着交叉,靶向瘦素轴在治疗上具有吸引力,尤其是在当前疗法无法治愈的晚期 PCa 中. 在这项研究中,我们发现瘦素是 PCa 中一种新的通用靶标,并且是第一个强调在 PCa 细胞和暴露于雄激素剥夺的患者肿瘤中增加的肿瘤内瘦素和瘦素受体 (LEPR) 表达,正如在患者的 转移性和去势抵抗性 (CRPC) PCa 肿瘤。我们还揭示了世界首个临床前证据,证明了使用 Allo-aca(一种有效、特异性和安全的 LEPR 肽拮抗剂)靶向瘦素信号传导阻滞的显着功效。在携带 LNCaP 异种移植物的小鼠中,Allo-aca 抑制肿瘤生长并延迟进展为 CRPC,肿瘤血管减少,肿瘤细胞凋亡、转录/翻译和能量学途径改变,被确定为支持抗肿瘤功效的潜在机制。我们强调 LEPR 阻断结合雄激素轴抑制代表了一种有前途的新治疗策略,对于晚期 PCa 治疗至关重要。使用 Allo-aca,一种有效、特异性和安全的 LEPR 肽拮抗剂。在携带 LNCaP 异种移植物的小鼠中,Allo-aca 抑制肿瘤生长并延迟进展为 CRPC,肿瘤血管减少,肿瘤细胞凋亡、转录/翻译和能量学途径改变,被确定为支持抗肿瘤功效的潜在机制。我们强调 LEPR 阻断结合雄激素轴抑制代表了一种有前途的新治疗策略,对于晚期 PCa 治疗至关重要。使用 Allo-aca,一种有效、特异性和安全的 LEPR 肽拮抗剂。在携带 LNCaP 异种移植物的小鼠中,Allo-aca 抑制肿瘤生长并延迟进展为 CRPC,肿瘤血管减少,肿瘤细胞凋亡、转录/翻译和能量学途径改变,被确定为支持抗肿瘤功效的潜在机制。我们强调 LEPR 阻断结合雄激素轴抑制代表了一种有前途的新治疗策略,对于晚期 PCa 治疗至关重要。肿瘤中的能量学被确定为支持抗肿瘤功效的潜在机制。我们强调 LEPR 阻断结合雄激素轴抑制代表了一种有前途的新治疗策略,对于晚期 PCa 治疗至关重要。肿瘤中的能量学被确定为支持抗肿瘤功效的潜在机制。我们强调 LEPR 阻断结合雄激素轴抑制代表了一种有前途的新治疗策略,对于晚期 PCa 治疗至关重要。
更新日期:2021-04-29
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