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Lisa K Philp, Anja Rockstroh, Melanie Lehman, Martin C Sadowski, Nenad Bartonicek, John D Wade, Laszlo Otvos Jr, and Colleen C Nelson

Adiponectin is an adipokine originally identified as dysregulated in obesity, with a key role in insulin sensitisation and in maintaining systemic energy balance. However, adiponectin is progressively emerging as having aberrant signalling in multiple disease states, including prostate cancer (PCa). Circulating adiponectin is lower in patients with PCa than in non-malignant disease, and inversely correlates with cancer severity. More severe hypoadiponectinemia is observed in advanced PCa than in organ-confined disease. Given the crossover between adiponectin signalling and several cancer hallmark pathways that influence PCa growth and progression, we hypothesised that targeting dysregulated adiponectin signalling may inhibit tumour growth and progression. We, therefore, aimed to test the efficacy of correcting the hypoadiponectinemia and dysregulated adiponectin signalling observed in PCa, a world-first PCa therapeutic approach, using peptide adiponectin receptor (ADIPOR) agonist ADP355 in mice bearing subcutaneous LNCaP xenografts. We demonstrate significant evidence for PCa growth inhibition by ADP355, which slowed tumour growth and delayed progression of serum PCa biomarker, prostate-specific antigen (PSA), compared to vehicle. ADP355 conferred a significant advantage by increasing time on treatment with a delayed ethical endpoint. mRNA sequencing and protein expression analyses of tumours revealed ADP355 PCa growth inhibition may be through altered cellular energetics, cellular stress and protein synthesis, which may culminate in apoptosis, as evidenced by the increased apoptotic marker in ADP355-treated tumours. Our findings highlight the efficacy of ADP355 in targeting classical adiponectin-associated signalling pathways in vivo and provide insights into the promising future for modulating adiponectin signalling through ADIPOR agonism as a novel anti-tumour treatment modality.

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Amy A Lubik, Jennifer H Gunter, Brett G Hollier, Susan Ettinger, Ladan Fazli, Nataly Stylianou, Stephen C Hendy, Hans H Adomat, Martin E Gleave, Michael Pollak, Adrian Herington, and Colleen C Nelson

IGF2 is a mitogenic foetal growth factor commonly over-expressed in cancers, including prostate cancer (PC). We recently demonstrated that insulin can activate de novo steroidogenesis in PC cells, a major pathway for reactivation of androgen pathways and PC progression. IGF2 can activate the IGF1 receptor (IGF1R) or insulin receptor (INSR) or hybrids of these two receptors. We therefore hypothesized that IGF2 may contribute to PC progression via de novo steroidogenesis. IGF2 mRNA but not IGF2 receptor mRNA expression was increased in patient samples during progression to castrate-resistant PC as was immunoreactivity to INSR and IGF1R antibodies. Treatment of androgen receptor (AR)-positive PC cell lines LNCaP and 22RV1 with IGF2 for 48 h resulted in increased expression of steroidogenic enzyme mRNA and protein, including steroid acute regulatory protein (StAR), cytochrome p450 family member (CYP)17A1, aldo–keto reductase family member (AKR)1C3 and hydroxysteroid dehydrogenase (HSD)17B3. IGF2 treatment resulted in increased steady state steroid levels and increased de novo steroidogenesis resulting in AR activation as demonstrated by PSA mRNA induction. Inhibition of the IGF1R/INSR signalling axis attenuated the effects of IGF2 on steroid hormone synthesis. We present a potential mechanism for prostatic IGF2 contributing to PC progression by inducing steroidogenesis and that IGF2 signalling and related pathways present attractive targets for PC therapy.

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Lisa K Philp, Anja Rockstroh, Martin C Sadowski, Atefeh Taherian Fard, Melanie Lehman, Gregor Tevz, Michelle S Libério, Charles L Bidgood, Jennifer H Gunter, Stephen McPherson, Nenad Bartonicek, John D Wade, Laszlo Otvos, and Colleen C Nelson

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.