Abstract 2133: In vivo efficacy of PSMA ADC in castration-resistant prostate cancer.
Authors: DiPippo Vincent A. , Nguyen Holly M. , Vessella Robert L. , Coleman Ilsa M. , Nelson Peter S. , Olson William C. , Corey Eva 
Published: August 2014

Abstract
Docetaxel treatment prolongs survival of patients with castration-resistant prostate cancer (CRPCa); however, the overall survival advantage still remains low. Antibody-drug conjugates (ADCs) have proven to be a viable approach for targeting cytotoxic agents to tumor cells to increase efficacy and minimize negative side effects. Prostate-specific membrane antigen (PSMA) is expressed by CRPCa cells and neovasculature surrounding non-prostatic solid tumors, and is currently under investigation as a therapeutic target. The objective of our studies was to evaluate the efficacy of an investigational agent, PSMA ADC, consisting of a fully human anti-PSMA antibody linked to monomethylauristatin E (MMAE) to inhibit CRPCa in a preclinical setting.
LuCaP 96CR, a model of CRPCa, was used in our study. Animals bearing subcutaneous LuCaP 96CR were treated for four weeks, once weekly with PSMA-ADC or with PSMA antibody and free MMAE. PSMA ADC significantly decreased tumor volumes in the high-PSMA expressing LuCaP 96CR. Tumor volume (TV) of the ADC treated groups were only 10-14% of TV in the control group and only 2-3% at the time of sacrifice. The inhibition of tumor growth was more pronounced with the PSMA ADC treatment than with the unconjugated antibody and free MMAE. The inhibitory effects lasted for six weeks after cessation of the treatment when the animals were sacrificed. Importantly, no significant negative side effects were associated with the PSMA ADC treatment. The effects of PSMA ADC on additional xenografts with moderate and low PSMA expression, including those derived from soft tissue and bone metastases, are currently under investigation. We also performed a gene expression analysis of 24 LuCaP xenografts that reflect the highly diverse and heterogeneous nature of PCa in patients. This analysis revealed associations between the expression of PSMA and a number of genes involved in glutamate and glutamate decarboxylase pathways (i.e., glutamate dehydrogenase (GLUD1 and GLUD2; and GAD1 respectively) suggesting potential pathways associated with PSMA function.
In summary PSMA ADC possesses potent antitumor activity in the LuCaP 96CR model with no significant negative side effects. Furthermore, correlates of PSMA expression may suggest a biological role of PSMA within the tumor environment influencing survival, proliferation and migration of tumor cells by alterations in the glutamatergic pathway. Evaluation of PSMA ADC efficacy in additional clinically relevant LuCaP models is ongoing, as well as investigation of the biology of PSMA in CRPCa.
Citation Format: Vincent A. DiPippo, Holly M. Nguyen, Robert L. Vessella, Ilsa M. Coleman, Peter S. Nelson, William C. Olson, Eva Corey. In vivo efficacy of PSMA ADC in castration-resistant prostate cancer. [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 2133. doi:10.1158/1538-7445.AM2013-2133