7427 Cellular Senescence As A Pro-Tumorigenic Process And Therapeutic Target In Adrenocortical Carcinoma

Abstract

Abstract Disclosure: L. Smith: None. K. Warde: None. S. Haston: None. J. Martinez-Barbera: None. K. Basham: None. Adrenocortical carcinoma (ACC) is a rare, yet highly aggressive malignancy that arises in the adrenal cortex. Advanced age is a major risk factor for ACC, with the peak age incidence between 50 and 60 years old. Older individuals above age 50 also have significantly worse survival outcomes. A better understanding of how aging contributes to the development and progression of ACC will uncover new treatment strategies. A major hallmark of aging is the systemic accumulation of senescent cells. While senescent cells have been implicated in various age-related diseases, including cancer, their role in ACC remains poorly understood. ACC tumors from older patients have an enrichment of senescence-associated gene signatures. Moreover, advanced ACC patients are treated with etoposide, doxorubicin, and cisplatin (EDP), which are chemotherapies that induce senescence. While EDP offers short-term benefit in some patients, more than half will progress within 6-months. We hypothesize that the accumulation of senescent cells that arise after EDP treatment are ultimately tumor-supportive long-term. As a result, we postulate that the use of senolytic compounds that clear away senescent cells after EDP treatment will lead to improved survival outcomes for ACC patients. We developed a new ACC mouse model that provides a window to study the role of senescence in ACC tumor progression and treatment. Our model is based on adrenal specific loss of ZNRF3, which is a Wnt inhibitor that is frequently inactivated in human ACC tumors. Despite early adrenal hyperplasia, we showed that Znrf3 conditional knockout (cKO) mice do not develop adrenal tumors until 18-months of age, which corresponds to the peak age incidence in humans. Additionally, the adrenals of Znrf3 cKO mice show a robust senescence activation phenotype that precedes adrenal tumorigenesis. We hypothesize that the accumulation of senescent cells is pro-tumorigenic long-term. To test our hypothesis, we combined Znrf3 cKO mice with a newly established mouse model that enables selective ablation of senescent cells (ZKO-FDR mice). Ongoing aging studies will determine whether the removal of early and late senescent cells in ZKO-FDR mice reduces adrenal tumorigenesis. Further, we established new primary tumor cell lines from aged ZKO-FDR mice. These cell lines will facilitate testing of the pro-tumor mechanisms of senescence. Additionally, they will permit the removal of senescent cells, both genetically and pharmacologically with senolytics, as a new treatment strategy in ACC. Overall, this project aims to investigate the pro-tumor biology of age- and therapy-induced senescence in ACC. Results from these studies will advance our understanding of senescence in cancer and aid in the development of new therapeutic strategies for ACC, including senolytics. Presentation: 6/2/2024