Philip Stewart Low

Abstract 4495: Small molecule approach for targeting tumor-associated macrophages via a functional FRβ

Tumor-associated macrophages (TAMs) are considered an attractive target for oncotherapy because of their important role in tumor microenvironment. While TAMs mostly arise from inflammatory blood monocytes, they become quickly programmed to the pro-tumor phenotype. In response to tumor-derived factors, these M2-biased TAMs are essentially tumor helper cells, as both cancer cells and TAMs promote each another through a paracrine signaling loop involving epidermal growth factor and colony stimulating factor-1. This important cellular interaction is critical at all stages of tumor progression including angiogenesis, invasion, growth and metastasis. In recent years, TAMs (CD68+, CD163+) have been found to express a functional folate receptor-β (FRβ) that displays high-affinity ligand binding and subsequent ligand-initiated endocytosis. FRβ-expressing TAMs are present in various cancer subtypes, the perivascular region, and the tumor invasive front. The abundance of FRβ+ TAMs has been linked to poor patient survival in pancreatic ductal adenocarcinoma. In the present study, we first characterized the phenotype of FRβ+ TAMs ex-vivo from both syngeneic and xenographic tumor models (breast, lung, melanoma, and pancreatic cancers). Using thioglycollate-elicited macrophages as positive controls, we estimated FRβ levels on TAMs with monoclonal antibodies and functional folate ligands. Using a ligand conjugation approach, we focused on targeting FRβ+ TAMs in tumors arising from cancer cells that do not express functional FR themselves. Preliminary proof-of-concept was established in the highly aggressive FR-negative 4T1 mammary tumor with a folate-targeted DNA alkylating agent. In addition, immunohistochemical analysis showed high FRβ expression in human anaplastic thyroid cancer, a TAM-rich disease with very poor prognosis. Collectively, our data suggest that targeting a TAM-rich cancer via FRβ may be a viable therapeutic approach with potential applications in FR-negative tumors. Citation Format: Leroy W. Wheeler, Yingjuan Lu, Vicky Cross, Alex Lloyd, Nikki Parker, Longwu Qi, Kevin Wang, Ian Wang, Spencer Hahn, Jeremy Vaughn, Iontcho P. Vlahov, Philip S. Low, Christopher P. Leamon. Small molecule approach for targeting tumor-associated macrophages via a functional FRβ. [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 4495. doi:10.1158/1538-7445.AM2015-4495