Abstract B015: A novel Cluster 3 Endometrial Cancer PDX model to test hormone therapy regimens

Abstract

Abstract Endometrial cancer is the most commonly diagnosed gynecologic cancer and continues to rise in incidence and mortality rates worldwide. With the evaluation of large datasets including the TCGA, endometrial cancers have been subdivided into four different cluster groups based on molecular characteristics. The most common subtype of endometrial cancer is the Cluster 3 category, demarcated by the expression of estrogen receptors (ER) and progesterone receptors (PR) with the potential to respond to hormonal therapy. However, Cluster 3 tumors frequently lose hormone receptor expression over time, particularly PR, making them resistant to treatment. Although numerous cell line models exist to study this disease, there is a need for improved models to select best treatment options for the specific types of endometrial cancers. Here, we describe the development of an endometrial cancer patient derived xenograft (PDX), EC-PDX3. The initial tumor from which EC-PDX3 was derived was a low-grade endometrioid endometrial carcinoma that contained a low number of somatic copy number alterations. The tumor initially tested robustly positive for both ER and PR in the donor patient as well as in initial passages in athymic mice, making this model valuable for hormone therapy research. In these studies, EC-PDX3 cells were grown within immunodeficient NSG mice. We performed H&E, ER and PR staining prior to experimentation and found that while ER remained highly positive, PR levels were significantly downregulated, indicating the development of a hormone resistant state similar to that occurring in patients over time. To determine if these cells respond to hormonal therapy and if PR expression could be induced, mice were initially treated with estradiol to enhance PR expression. Next, mice were further treated with progesterone or onapristone, an experimental progestin agonist/antagonist with previously reported encouraging activity in advanced endometrial cancer in phase I and II trials. Tumors were measured weekly to determine hormone effects on cancer growth. Mice treated with estradiol alone showed substantially larger tumor growth as compared to the estradiol + progesterone and estradiol + onapristone treatment groups, indicating that hormone sensitivity was likely re-instated. RNA sequencing using Ishikawa cells in culture revealed the transcriptional effects of estradiol, progesterone and onapristone which complement the data obtained from EC-PDX3 bearing mice treated similarly. These studies identify interesting growth inhibitory effects of onapristone in endometrial cancer cells primed with estradiol including the significant induction of the cell cycle regulators such as p21 and genes involved in apoptosis. In addition, EC-PDX3 provides a model to assess hormonal therapy in Cluster 3 tumors that initially respond but develop resistance to treatment over time. Citation Format: Kimberly K. Leslie, Lane E. Smith, Jamie Padilla, Adrian Quintana. A novel Cluster 3 Endometrial Cancer PDX model to test hormone therapy regimens [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B015.