Abstract P5-17-10: Anti-progranulin (GP88) antibody AG01 inhibitory effect on the growth of triple negative breast cancer cells

Abstract Background: Triple negative breast cancer (TNBC) is characterized by invasiveness and short survival. Identifying novel TNBC targeted therapies to potentiate standard of care (SOC) therapy, is an unmet need. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC). PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes such as progression of disease and shortened survival. Since PGRN/GP88 expression is elevated in 30% TNBC, we investigated the effect of inhibiting PGRN/GP88 effect on the proliferation and tumor growth of triple negative breast cancer cells. Methods: For this purpose, we have developed a neutralizing anti-human PGRN/GP88 monoclonal antibody AG01 and examined its effect on the proliferation, migration, signaling pathway activation and biomarker expression of two TNBC cell lines MDA-MB-231 and HS578-T expressing PGRN/GP88, both in vitro and in vivo. Results: The inhibition of PGRN/GP88 action by AG01 treatment reduced proliferation and migration in a dose-and time-dependent fashion in MDA-MB-231 and HS578-T cells. Western blot analysis showed decreased expression of phosphorylated protein kinases p-Src, p-AKT and p-ERK involved in proliferation and survival upon AG01 treatment for both cell lines. Transwell assay showed that AG01 treatment inhibited migration and invasion in a dose-dependent fashion. Microarray analysis of several oncoproteins in cells treated with AG01 or control antibody demonstrated the inhibition of the expression of several markers of migration and angiogenesis. In vivo xenograft studies with MDA-MB-231 cells injected in athymic nude mice showed that AG01 treatment inhibited tumor growth as well as Ki67 expression, mitotic index and microvessel counts when compared to antibody control treated mice. In vivo dose response of AG01 in MDA-MB-231 tumor bearing mice will be provided. Conclusion: TNBC is a disease with poor prognosis in need of novel targeted therapeutic solutions. PGRN/GP88 represents a therapeutic target for TNBC with two companion diagnostics (tissue test and ELISA to measure GP88 circulating levels). Blocking PGRN/GP88 with AG01 antibody treatment will provide novel targeted therapeutic option for TNBC which could address the issue of toxicity, and unresponsiveness associated with SOC. This work is supported by a grant CA 224718 from the National Cancer Institute to GS. Citation Format: Ginette Serrero, Rupa Guha, Jianping Dong, Binbin Yue. Anti-progranulin (GP88) antibody AG01 inhibitory effect on the growth of triple negative breast cancer cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-17-10.