Abstract 2365: Targeting M2-tumor associated macrophages (M2-TAMs) in prostate cancer

Abstract

Abstract Prostate cancer is a leading cause of cancer-related deaths of men in the U.S., and in the past year, over 30,000 men died from this disease. While localized prostate cancer is highly treatable by surgical resection and radiation, cancer that has metastasized remains incurable. Alternatively activated macrophages, also known as M2-macrophages, primarily scavenge debris and in the process, promote angiogenesis and wound repair. M2-macrophages are phenotypically similar to M2-tumor associated macrophages (M2-TAMs) have been reported to associate with solid tumors such as prostate cancer to facilitate epithelial to mesenchymal transition (EMT), tumor invasiveness, metastasis, and resistance to therapy. As an invasive species within the tumor microenvironment, this makes M2-TAMs an ideal therapeutic target in prostate cancer. The purpose of this project is to develop novel therapeutics that will directly target M2-TAMs for destruction and subsequently attenuate prostate tumor growth and progression. The central hypothesis of this study is to determine if targeting of M2-TAMs using specific surface antigens will be an effective therapy for lethal prostate cancer and potentially, other cancers. Our study will first elucidate M2-TAM biology, including both a study of known M2-TAM cell surface antigen markers expressed in human prostate cancers as well as rigorous tests to target these markers for anti-tumor cell efficacy using relevant model systems. Functional experiments will then be done in vitro using primary antibodies that are bound by a saporin-conjugated secondary antibody and also, in vivo by utilizing human xenograft mouse models. We will also assess internalization of armed antibodies, M2-TAM cell death, M2-TAM functionality, and EMT status of PCa tumors after targeting. This will be followed by target validation using tissues from rapid autopsies and surgical specimens supplied by the Department of Urology at Johns Hopkins University School of Medicine. By targeting specific markers on M2-TAMs, we predict that this targeting will provide a better prognosis for patients who have been diagnosed with lethal prostate cancer. Modification of targeted ligands and drug combinations will produce a flexible platform for cancer therapy. The studies described here represent an underdeveloped frontier in cancer therapeutics and outline a method of altering the tumor immune microenvironment. If successful, antibodies used against specific M2-TAM surface markers will be constructed into antibody drug conjugates (ADCs). Citation Format: Jelani C. Zarif, James R. Hernandez, Kris F. Sachsenmeier, Robert E. Hollingsworth, Kenneth J. Pienta. Targeting M2-tumor associated macrophages (M2-TAMs) in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2365. doi:10.1158/1538-7445.AM2015-2365