Philp Lisa K, Rockstroh Anja, Sadowski Martin C, Taherian Fard Atefeh, Lehman Melanie, Tevz Gregor, Libério Michelle S, Bidgood Charles L, Gunter Jennifer H, McPherson Stephen, Bartonicek Nenad, Wade John D, Otvos Laszlo, Nelson Colleen C
Australian Prostate Cancer Research Centre - Queensland, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Princess Alexandra Hospital, Translational Research Institute, Brisbane, Queensland, Australia.
Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Endocr Relat Cancer. 2021 Apr 29;28(5):353-375. doi: 10.1530/ERC-20-0405.
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.
高瘦素血症是抑制前列腺癌（PCa）雄激素轴的药物已明确的治疗副作用，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与多种癌症促进标志通路（包括生长、增殖、迁移、血管生成、代谢和炎症）之间存在显著交叉，靶向瘦素轴在治疗上具有吸引力，尤其是在晚期PCa中，目前的疗法无法治愈。在本研究中，我们发现瘦素是PCa中的一个新的通用靶点，并且首次强调在接受雄激素剥夺的PCa细胞和患者肿瘤中，肿瘤内瘦素和瘦素受体（LEPR）表达增加，这在转移性和去势抵抗性（CRPC）PCa患者的肿瘤中也有观察到。我们还揭示了世界上首个临床前证据，即使用一种强效、特异性和安全的LEPR肽拮抗剂Allo-aca证明了靶向瘦素信号阻断的显著疗效。在携带LNCaP异种移植瘤的小鼠中，Allo-aca抑制肿瘤生长并延缓向CRPC的进展，肿瘤血管减少以及肿瘤中凋亡、转录/翻译和能量代谢途径改变被确定为抗肿瘤疗效的潜在机制。我们强调LEPR阻断与雄激素轴抑制相结合代表了一种有前景的新治疗策略对于晚期PCa治疗至关重要。
