Abstract 2054: GP88 (Progranulin) is a therapeutic and prognostic target for Non-Small Cell Lung Carcinoma.
Authors: Serrero Ginette , Xia Guanjun , Dong Jianping , Yue Binbin , Schech Amanda , Hawkins Douglas , Reisman David , Bejarano Pablo , Hayashi Jun 
Published: August 2014

Annually, about 220,000 patients are diagnosed with lung cancer in the US and 150,000 die of the disease. Advanced and recent therapeutic development in NSCLC addresses targets found in small percentages of patients, thereby emphasizing the need for continued discoveries of additional targets of lung cancer, in order to develop of novel therapies and diagnosis. We have investigated the role of the autocrine growth and survival factor GP88 (Progranulin) on the biology of Non-Small Cell Lung Carcinoma (NSCLC). Previously, GP88 had been shown to play a critical role in the proliferation and survival of breast cancer. Pathological studies with 600 cases of estrogen receptor positive invasive ductal carcinoma in correlation with clinical outcome data have also shown that GP88 tissue expression was associated with a 4-fold increased risk of recurrence and a 2.5-fold increase in mortality whereas inhibition of GP88 action by a neutralizing antibody resulted in inhibition of tumor formation of breast adenocarcinoma in vivo. In the present study, we examined the role of GP88 in NSCLC. Examination of GP88 protein expression by immunohistochemistry was carried out with formalin fixed paraffin embedded sections of lung cancer cases. Results showed that both human adenocarcinoma and squamous carcinoma stained positive for GP88 whereas normal lung tissues were negative. Pathological studies of tissue GP88 expression by IHC in 85 stage 1 and 2 NSCLC tumors in correlation with clinical outcomes demonstrated that high GP88 expression was associated with a 4-fold increase in the risk of recurrence (p=0.0004) indicating that GP88 is a prognostic factor for NSCLC. Based on these observations, expression and action of GP88 in NSCLC were examined using two representative human NSCLC cell lines A549 and H1299. Inhibition of GP88 expression by GP88 SiRNA resulted in an inhibition of cell migration and proliferation of these cells. Similarly, neutralization of GP88 action by treating the cells with AG1, an anti-human GP88 neutralizing monoclonal antibody expressed in recombinant form also inhibited cell proliferation and migration. Based on these results, studies were carried out to examine the effect of AG1 antibody on NSCLC tumor formation in nude mice. Preclinical studies show that AG1 treatment inhibits tumor formation by 30-50% when used as a single agent or in combination therapy with chemotherapeutic drugs used in the standard of care in NSCLC. These data to be presented here point out that GP88 is a novel therapeutic and prognostic target and provide new opportunities for targeted therapy with companion diagnostic for NSCLC.

Citation Format: Ginette Serrero, Guanjun Xia, Jianping Dong, Binbin Yue, Amanda Schech, Douglas Hawkins, David Reisman, Pablo Bejarano, Jun Hayashi. GP88 (Progranulin) is a therapeutic and prognostic target for Non-Small Cell Lung Carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2054. doi:10.1158/1538-7445.AM2013-2054