Abstract 4743: Defining the impact of anti-androgen pathway inhibitors on ABI1, dendritic spines and mouse behavior

Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer-related deaths among American men. Following radiation therapy and surgery, patients are often treated with androgen deprivation therapy (ADT) or anti-androgen drugs to suppress tumor growth, as prostate cancer is highly androgen-dependent. However, emerging evidence highlights significant cognitive side effects, including dementia and behavioral changes, associated with anti-androgen treatments. While clinical trials are investigating these ‘treatment-induced’ cognitive deficits, the underlying mechanisms remain poorly understood. Our previous work revealed that the Androgen Receptor (AR) regulates Abelson Protein 1 (ABI1) expression in prostate tumors. ABI1, a key stabilizer of the WAVE complex, plays a critical role in actin polymerization and cytoskeletal reorganization. In dendritic spines, ABI1 supports the dynamic remodeling of the cytoskeleton essential for synaptic plasticity, a fundamental process underlying learning and memory. Disruption of ABI1 in hippocampal neurons results in abnormal dendritic spine morphology and impaired synapse formation, but there are no genetic studies on the role of Abi1 in cognitive performance in mouse models. Androgen deprivation, through surgical castration or ADT, has been shown to impair memory and behavior in mice. Given that ABI1 expression is downregulated by anti-AR therapy in prostate tumors, we hypothesize that ABI1 is similarly regulated by androgens in dendritic spines. We propose that AR suppression by ADT leads to reduced ABI1 expression in dendritic spines, contributing to cognitive and behavioral impairments in patients undergoing ADT. To test this hypothesis, we utilized a novel Abi1-selective knockout mouse model developed in our lab to explore the effects of ABI1 disruption on dendritic spines and behavior. Additionally, we compared dendritic spine morphology and ABI1 levels in the hippocampi of mice treated with anti-AR drugs, such as enzalutamide, or subjected to surgical castration. These results are being analyzed alongside findings from mice with genetic ABI1 disruption. This study provides critical insights into the role of ABI1 in dendritic spine dynamics and synaptic plasticity, uncovering a potential mechanistic link between ADT and cognitive dysfunction. Our findings aim to define the molecular basis of treatment-related cognitive deficits in PCa patients and may guide the development of strategies to mitigate these side effects. Citation Format: Anna Seidl, Kevin M. Lin, Maria A. Ortiz, Leszek Kotula. Defining the impact of anti-androgen pathway inhibitors on ABI1, dendritic spines and mouse behavior [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4743.