Abstract
The 88 kDa glycoprotein GP88 (Progranulin, PCDGF, acrogranin) is the largest member of the granulin/epithelin family of growth modulators identified as a driver of tumorigenesis. GP88 (PGRN) was also shown to be overexpressed in invasive ductal carcinoma (IDC)whereas it was negative in benign tumors and normal mammry epithelial tissue, thereby establishing GP88 as a therapeutic and diagnostic target in breast cancer (BC). Our laboratory has developed validated tools to measure GP88 in tumor biopsies and biological fluids as well as blocking its action. WE showed that GP88 was secreted and detected in the serum of BC patients at an increased level when compared to healthy subjects. Pathological studies with 530 cases of ER+ IDC with clinical outcomes showed that GP88 tumor expression was an independent prognostic indicator of recurrence in early stage BC patients. Training study followed by an independent validation study demonstrated that high GP88 tissue expression (GP88 3+) was associated with a 4-fold increase in risk of recurrence at 5 years. A neutralizing anti-GP88 antibody AG1 was expressed in a high yield CHO cell line was developed. The present study examined the effect of AG1 in letrozole resistant cell line AGLetR developed by long term selection in letrozole supplemented medium. This cell line showed decreased letrozole responsiveness in vivo and therefore constituted an excellent model for investigating letrozole resistance in vitro as well as in vivo. Here we report the results of studies investigating the effect of various doses of AG1 on LetR tumor development in combination with letrozole for AGLetR. We show that treatment with AG1 (10 mg/kg i.p.) in combination with letrozole was efficient to maintain long term responsiveness and inhibit tumor growth. Letrozole alone (5mg/kg) was unable to inhibit tumor growth and showed a doubling of tumor volume. Interestingly, long term combination treatment lead to tumor regression and inhibited tumor growth.
These data suggest that inhibiting GP88 could provide a novel and alternative therapeutic strategy for patients with resistance to anti-estrogen therapy, being tamoxifen or letrozole.
This works is supported by 2R44CA124179, HHSN 261201200060C, and HHSN2612014400C from NCI.
Citation Format: Serrero G, Dong J, Yue B, Hicks D, Hayashi J. Combination of anti-progranulin (GP88/PGRN) antibody and letrozole inhibits tumor formation of letrozole resistant breast cancer cell lines. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-12.
Volume 76, Issue 4 Supplement
