Abstract 2682: Targeting phosphoglycerate dehydrogenase (PHGDH) in combination with tamoxifen reduces hormone receptor positive breast cancer growth in vivo

Abstract

Abstract Breast cancer afflicts thousands of individuals every year and is clinically diagnosed in various subtypes, including hormone receptor positive (HR+ BC). Significant strides have been made in treating HR+ BC through the development of endocrine therapies, such as tamoxifen, fulvestrant, and aromatase inhibitors. While these have improved the survival outcomes of these patients, many eventually relapse and, ultimately succumb to metastatic endocrine resistant disease. Subsequent work has identified various cellular pathways contributing to endocrine resistance, including alterations in cellular metabolism. We previously demonstrated that de novo serine synthesis (SSP) is increased in endocrine resistant cell types and genetic disruption of SSP enzymes impacts tamoxifen sensitivity. Further, elevated transcript expression is inversely correlated with survival outcomes in HR+ BC patients treated with tamoxifen. From this, we aimed to assess whether pharmacological targeting of SSP activity in combination with tamoxifen affects the growth of HR+ BC in vivo. We confirmed the presence of ER-alpha in three distinct patient derived xenograft (PDX) models and found varying levels of both phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1), which are the first and second enzymatic steps in the SSP pathway, respectively. In our efficacy studies, we initially found differential sensitivity to tamoxifen administration across the PDX models. While treatment with a PHGDH inhibitor (PHGDHi) had no anti-tumor activity against an endocrine-sensitive PDX, it moderately reduced the growth of endocrine resistant PDX tumors. Notably, combinatorial treatment resulted in a substantial decrease in tumor growth in all three models compared to single agents alone. Together, these data suggest that targeting of SSP activity in combination with endocrine therapies may be a promising therapeutic strategy in HR+ BC. Citation Format: Brian F. Clem, Yoannis Imbert-Fernandez, Belinda Petri, Carolyn Klinge. Targeting phosphoglycerate dehydrogenase (PHGDH) in combination with tamoxifen reduces hormone receptor positive breast cancer growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2682.