Abstract 4514A: Antibody to Progranulin (Anti-GP88) potentiates tamoxifen and letrozole effect in estrogen receptor positive breast cancer cells

Abstract

Abstract GP88 (Progranulin, PCDGF, acrogranin), the largest member of the granulin/epithelin family was originally characterized in our laboratory as a driver of tumorigenesis. Published evidence showed that 1) GP88 expression increases with tumorigenesis; 2) in ER+ breast cancer (BC) ells, GP88 stimulates proliferation and its overexpression confers estrogen independence and resistance to several anti-estrogens and aromatase inhibitor; 3) Antisense inhibition of GP88 expression inhibited proliferation in vitro and in vivo; 4) In Her-2 overexpressing BC, GP88 stimulated Her-2 phosphorylation and conferred trastuzumab resistance; 5) GP88 is expressed in 80% invasive ductal carcinoma (IDC) and 60% of ductal carcinoma whereas it is negative in lobular carcinoma and normal mammary epithelial cells; 6) GP88 is secreted and detected in the serum of breast cancer patients at an increased level when compared to healthy subjects. As GP88 represents an ideal therapeutic and diagnostic target in breast cancer, we have developed tools to measure GP88 in tumor biopsies and biological fluids as well as blocking its action. Pathological studies with 530 cases of ER+ IDC showed that GP88 tumor expression measured by immunohistochemistry was an independent prognostic indicator of recurrence in early stage breast cancer 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. Since GP88 shows not only diagnostic but also therapeutic potentials, we developed a neutralizing anti-GP88 antibody AG1 that inhibits GP88 biological effect (proliferation and migration) in a dose-dependent fashion in vitro. AG1 was expressed in a high yield CHO cell line and formulated. Here we examined the effect of AG1 on responsiveness of breast cancer cells to two drugs commonly used in ER+ patients tamoxifen and letrozole. For these studies, we have developed from a tamoxifen sensitive and from a letrozole sensitive cell ER+ BC cell lines, tamoxifen resistant (TamR) and letrozole- resistant (LetR) cell lines by long term in vitro cell culture selection. Here we report the results of studies investigating the effect of various doses of AG1 on TamR and LetR tumor development alone or in combination with the anti-estrogen drugs. We show that treatment with AG1 (5 mg/kg and 10 mg/kg i.p.) in ombination with tamoxifen or letrozole increased the effect of tamoxifen and letrozole alone, maintained long term responsiveness to tamoxifen or letrozole and inhibited tumor growth. Analysis of anti-GP88 mode of action was examined. These data suggest that inhibiting GP88 provides a novel and alternative therapeutic strategy for patients with resistance to anti-estrogen therapy, being tamoxifen or letrozole. Support: 2R44CA124179 and HHSN 261201200060C from NCI and 02-2013-018 from the Avon Foundation. Citation Format: Ginette Serrero, Jianping Dong, Jorge Marquez, Binbin Yue, Jun Hayashi. Antibody to Progranulin (Anti-GP88) potentiates tamoxifen and letrozole effect in estrogen receptor positive breast cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4514A. doi:10.1158/1538-7445.AM2014-4514A