Investigating age-dependent factors in the development and treatment of adrenal cancer

Aging is the strongest risk factor for cancer, yet the mechanisms linking aging to tumor development remain poorly defined. Our work focuses on adrenocortical carcinoma (ACC), a rare but aggressive cancer with peak incidence after age 50 and limited treatment options. We developed the first ACC mouse model that mirrors the age dependence of the human disease and found that age-associated tumors retain long-lived senescent adrenal cortex cells. Senescence, a hallmark of aging, was traditionally viewed as tumor-suppressive due to its prolonged growth arrest. However, recent evidence indicates that some senescent cells can become protumorigenic, particularly when they persist long-term. This has important clinical implications given the widespread use of conventional chemotherapy agents that trigger therapy-induced senescence (TIS), including in ACC where the standard-of-care uses etoposide, doxorubicin, and cisplatin (EDP). Consequently, TIS may create reservoirs of tumor cells primed for recurrent growth, leading to worse patient outcomes long-term. To address this clinical problem, senolytic drugs that kill senescent cells could be repurposed for cancer therapy, but this has never been tested in ACC. Our overall objective is to determine how long-term senescent cells that accumulate with age promote adrenal tumor initiation and progression, and to develop senolytic strategies to kill senescent ACC cells following TIS. Our central hypothesis is that persistent senescent cells become protumorigenic through an age-dependent increase in the dosage of Wnt signaling, which is targetable using senolytics. In Aim 1, we will use genetic and pharmacological tools to selectively ablate senescent cells at different age-dependent stages and measure ACC tumorigenesis. We will then test whether hyperactivation of Wnt signaling facilitates senescence release and tumorigenesis. In parallel, we will use spatial transcriptomics to develop a high-resolution atlas of cellular senescence and the age-dependent changes in senescent cell states that enhance Wnt activation. In Aim 2, we will therapeutically target persistent senescent cells after TIS using senolytics. For these studies, we developed new ACC cell lines containing a live senescence reporter, which we will use to test the sensitivity and specificity of both novel and established senolytic strategies. We will then validate our results using human ACC models and an orthotopic tumor transplant model of primary ACC tumor growth and recurrence. Animal models are essential for this project because they uniquely enable the study of systemic, age-dependent physiological changes and immune interactions that regulate senescent cell behavior and tumorigenesis. To extend our findings to patients, we will use primary human ACC tumor samples to measure TIS clinically and identify predictors of high senescent burden where a senolytic has the highest potential benefit. Together, these studies will define how persistent senescence contributes to adrenal cancer, providing the preclinical rationale for senolytic therapies in ACC and helping to inform other age-related cancers. Project Number: 1R01CA308007-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Kaitlin Basham | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $581,686 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics B Study Section[MCTB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11367961