Novel Androgen Receptor PROTAC Degrader ARV-110 Ameliorates White Adipose Tissue and Kidney Structural Derangements in a Mouse Model of Polycystic Ovary Syndrome
Authors: Basnet Jelina , Rezq Samar , Huffman Alexandra , Asala Tolulope , Cardozo Licy , Romero Damian 
Published: May 2023

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. PCOS women often have increased central adiposity, insulin resistance, and renal injury. Hyperandrogenism is prevalent in PCOS women and is positively associated with metabolic dysfunction. Androgens bind to the androgen receptor (AR) to impart downstream transcriptional activity. Targeting the AR may alleviate PCOS complications, however the use of AR blockers is limited by their severe adverse effects in females thus safer alternative approaches are highly needed. ARV-110, a novel AR Proteolysis Targeting Chimera (PROTAC) degrader demonstrates high efficacy to prevent AR signaling in prostate cancer, however its efficacy in PCOS is unknown. Using a well-established hyperandrogenemic mouse model of PCOS, we aim to test the hypothesis that decreasing AR protein levels with ARV-110 will ameliorate androgen-mediated derangements in PCOS. Methods: Three-week old female mice (C57BL/6N) were implanted with Silastic tubes filled with the androgen dihydrotestosterone (DHT, 8mg, S.C., 90 days) or vehicle (n=6/grp). Four weeks post-DHT administration, mice were treated with ARV-110 (1 mg/kg/day, S.C.) for an additional 8 weeks. Body composition (EchoMRI) and the oral glucose tolerance test (OGTT) were assessed. Retroperitoneal fat (RPF) and kidney weights were measured by gravimetry. AR and extracellular matrix (ECM) remodeling marker MMP9 protein levels were assessed by Western blot, while the pro-fibrotic marker TGF-β was assessed by ELISA. Results: DHT mice showed significant (p<0.05) increases in body weight (27.3±0.6 vs 23.9±0.26 g), fat mass (4.2±0.6 vs 2.1±0.1 g), lean mass (21.6±0.2 vs 19.8±0.2 g), as well as RPF (244.4±37.4 vs 50.0±1.8 mg) and kidney weights (491.3±7.69 vs 303.1±5.5 mg) compared to controls. DHT increased fasting glucose (183.2±25.2 vs 141.5±9.9 mg/dL, p<0.05) and impaired OGTT (AUC:34557±6255 vs 23459±1896 mg.min/dL, p<0.05). ARV-110 treatment ameliorated all aforementioned DHT-mediated changes. On the molecular level, DHT mice had higher AR expression in RPF (1.5-fold) and kidney (2.5-fold), and higher MMP9 in both tissues (2- and 1.5-fold, respectively) indicating ECM remodeling. DHT had no significant effect on TGF-β in RPF but it upregulated TGF-β level in the kidney (2-fold, p<0.05). ARV-110 successfully decreased both RPF and renal AR protein levels by 70% in DHT mice compared to vehicle-treated DHT. Excitingly, while ARV-110 did not modulate RPF nor renal TGF-β levels, it completely abolished DHT-mediated MMP9 increase in both tissues. Conclusion and significance: Our findings suggest that DHT-mediated WAT expansion, kidney hypertrophy, and associated ECM remodeling are ameliorated by ARV-110 in DHT mice. These results highlight the pivotal role of AR in androgen-mediated and tissue-specific derangements common in PCOS. AR PROTACs could be a novel therapeutic approach to treat metabolic and renal dysfunction in PCOS.

Supported by National Institute of General Medical Sciences of the National Institutes of Health grant P20GM121334 (L.L.Y.C. and D.G.R.), and American Heart Association Predoctoral Fellowship 903804 (A.M.H.)

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.