Abstract 6804: Estrogen therapy alleviates cancer-associated cachexia in mouse models of both sexes

Abstract Cancer-associated cachexia (CAC) is a multifactorial wasting syndrome marked by progressive loss of skeletal muscle and adipose tissue, affecting up to 80% of patients with advanced cancers and directly contributing to 20-30% of cancer-related deaths. It not only reduces quality of life but also impairs tolerance to therapy and worsens prognosis. Despite its prevalence and impact, CAC remains under-investigated, and although several agents are under clinical evaluation, no FDA-approved treatments exist. The lack of effective therapies represents a critical unmet medical need, as current supportive measures offer little benefit once tissue wasting begins. Clinically, male patients experience more severe and frequent CAC than female patients, suggesting a protective role for female-specific factor(s). To explore this, C57BL/6 mice were inoculated subcutaneously with B16F10 melanoma or KPL (KrasG12D/+; p53-/-; Lkb1-/-) lung cancer cells, our two established models that recapitulate CAC features including severe anemia, muscle wasting, and adipose atrophy. Consistent with patients’ data, male mice inoculated with cancer cells also developed significantly more severe CAC features than female mice. To determine whether gonadal hormones influenced this difference, mice of both sexes underwent gonadectomy before tumor implantation. Interestingly, ovariectomy in females markedly worsened CAC symptoms and abrogated female protection, while castration in males produced no effect on severity of CAC, indicating that ovarian factors likely help protect against tissue wasting. Among these factors, 17β-estradiol (E2) was identified as a key candidate due to its known metabolic and tissue-preserving effects. Importantly, when male and ovariectomized female mice were treated with controlled-release E2 pellets before tumor challenge, E2 supplementation preserved skeletal muscle and subcutaneous white adipose tissue, though it had minimal impact on visceral fat and failed to reverse CAC-associated anemia. Thus, these new findings suggest that E2 signaling plays a protective role in CAC progression and could represent a novel therapeutic target. Given the availability of FDA-approved agents that modulate E2 pathways, further studies combining E2 with treatments such as erythropoietin (EPO) may offer new opportunities to address the urgent need for effective CAC therapies and improve outcomes for patients suffering from this devastating condition. Citation Format: Vincent T. Pham, Victoria Sanchez, Shaozi Fu, Yaxing Nie, Kasie Liu, Yu Luan, Lingtao Jin, Gang Huang. Estrogen therapy alleviates cancer-associated cachexia in mouse models of both sexes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6804.