👤 Authors: J E Hunt, C Lund, B Chen, A R Diaz, O Dmytriyeva, J Marcotorchino, K Löbner, K Mörl, N R Andersen, Z K J Ogueboule, E Frank, J Stöhr, D Meseguer, V Panajotova, J Roux, C Clemmensen, L Sylow, M Schneeberger, A G Beck-Sickinger, S L Pedersen, K Fosgerau
Novel Long-Acting Ghrelin Analogue PEP-064 Restores Energy Balance in C26 and Lewis Lung Carcinoma-Induced cachexia in Mice.
BACKGROUND
Cancer cachexia is a debilitating syndrome marked by involuntary weight loss resulting from reduced food intake and intricate metabolic reprogramming. Despite its high prevalence, cancer cachexia remains undertreated, with a lack of effective and approved pharmacotherapies.
Ghrelin has emerged as a therapeutic target for cancer cachexia due to its beneficial effects on energy balance. However, the clinical application of ghrelin is hampered by its short half-life.
In this study, we introduce PEP-064, a novel stabilized, long-acting and efficacious ghrelin analogue and assess its effects on C26-induced and Lewis lung carcinoma (LLC)-induced cachexia in mice.
METHODS
The in vivo efficacy of PEP-064 was evaluated in healthy CD-1 mice after repeated dosing for 7 days and in the C26 and LLC cancer cachexia mouse models. Additionally, the pharmacokinetic profile and whole brain neuronal activity mapping were conducted in healthy mice following a single subcutaneous injection of PEP-064.
Growth hormone secretion was measured in healthy rats following a single administration of PEP-064.
RESULTS
In healthy mice, PEP-064 exhibited a dose-dependent (100, 300 and 1000 nmol/kg) increase in both delta body weight (BW) and total food intake (FI) compared to the vehicle (BW: 2.7 g vs. 3.5, 4.8 and 5.3 g; FI: 50 g vs. 57 g, 60 and 70 g). In the C26 model, PEP-064 protected against loss of tumour-free (TF) BW (-1.2 g vs. 1.7 g, p < 0.0001), increased food intake (33 g vs. 41 g, p < 0.01), prevented losses in fat (-1.1 g vs. 0.9 g, p < 0.0001) and lean mass (-0.07 g vs. 0.4 g, p < 0.05) without affecting tumour growth.
In the LLC model, PEP-064 induced hyperphagia (52.2 g vs. 61.6 g, p < 0.0001) and protected against TF-BW loss (-1.4 g vs. - 0.01 g, p < 0.05) and fat mass loss (-0.9 g vs. 0.8 g, p < 0.0001). In mice, PEP-064 had a T 1/2 of 6.6 h and a T max at 4 h.
PEP-064 increased neuronal activity (c-Fos) in the hypothalamic and amygdala regions, with the tuberal nucleus of the hypothalamus showing the highest increase compared to the vehicle (p < 0.05). Lastly, circulating growth hormone was increased 20 min after subcutaneous PEP-064 dosing, peaking at 30 min at 93 ng/mL and returning to approximately baseline by 120 min.
CONCLUSIONS
The novel, long-acting and efficacious ghrelin analogue, PEP-064, restored energy balance in cancer cachexia by increasing food intake and body weight, preserving lean mass and increasing adiposity, without affecting tumour growth.
Considering the unmet medical need for safe and effective treatments for cachexia, our study demonstrates the feasibility of a long-acting ghrelin approach for treating cancer cachexia.
