Abstract 1934: Anti-Progranulin (GP88) antibody AG01 therapeutic effect in triple negative breast cancer invasiveness
Authors: Guha Rupa , Dong Jianping , Yue Binbin , Serrero Ginette 
Published: August 2018

Breast cancer (BC) is the second leading cause of death in women worldwide. 15-20% of BC is triple negative breast cancer (TNBC).This subtype is very important clinically because of its high, invasiveness and short metastasis-free survival. Because of the lack of ER, PR and Her2 receptors, TNBC patients cannot be treated with anti-estrogen or Her2 targeted therapies. Standard of care (SOC) includes chemotherapies like anthracyclines, cyclophosphamide, taxanes and radiation therapy. There is an unmet need for novel targeted therapies for TNBC that can be used as single agent or in combination to potentiate SOC therapy to avoid or reduce toxicity, non-specific effects and unresponsiveness. Therefore it is very important to identify biomarkers overexpressed in TNBC that play a critical role in TNBC invasiveness and can be used as therapeutic targets. Progranulin (PGRN, GP88) is a secreted glycoprotein autocrine growth/survival factor functions as a biological driver of tumor cell proliferation, tumorigenesis, survival, invasiveness and drug resistance in several cancers, including breast cancer (BC). In ER+ BC, GP88 stimulates proliferation and survival and its overexpression confers estrogen independence and anti-estrogen resistance. GP88 is overexpressed in ER+ BC and in TNBC. GP88 expression in ER+ tumor biopsies is an independent prognostic factor of recurrence. High GP88 is also found in 30% of TNBC. GP88 is secreted in the serum of BC patients at an increased level compared to healthy subjects. GP88 represents an important therapeutic and diagnostic target in breast cancer. We have developed a recombinant neutralizing anti-human progranulin monoclonal antibody AG01 that inhibits its biological effect in vitro and in vivo and has fulfilled IND-enabling activities including toxicology study in non-human primates. Since GP88 is associated with poor outcome in BC patients, we investigated AG01 effect on the proliferation, survival, migration and invasion of TNBC MDA-MB-231 cells that overexpress PGRN/GP88.. AG01 reduced cell proliferation, migration and invasion significantly in a dose and time-dependent fashion. Western blot analysis showed evidence of regulatory changes upon AG01 treatment such as decreased expression of Ki67, p-Src, p-AKT, p-FAK and p-MAPK in these cells. In addition, AG01 treatment significantly reduced MDA-MB-231 cell migration and cell invasion in transwell assays. These data will be presented here along with in vivo tumor inhibition study. PGRN/GP88 represents a potential therapeutic with companion diagnostic target to provide novel solutions in TNBC and address the issue of toxicity, non-specific therapy and unresponsiveness often associated with SOC. We plan to further our in vivo studies based on on-going anti-PGRN pharmacokinetic study in athymic nude mice to help in the selection of in vivo efficacious AG01 dose in upcoming human phase 1 clinical study.

Citation Format: Rupa Guha, Jianping Dong, Binbin Yue, Ginette Serrero. Anti-Progranulin (GP88) antibody AG01 therapeutic effect in triple negative breast cancer invasiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1934.