Abstract 4182: Impacting early events in metastatic spread: Targeted therapeutics to disrupt formation of the pre-metastatic niche and development of lung metastases

There is now growing interest in understanding the early events which lead to the successful formation of solid tumor metastatic spread because this information may lead to early interventional approaches. Bone marrow derived cells (BMDCs) of various lineages are gradually being identified as central to the ongoing growth of the primary tumor as well as the successful development of metastasis. Upon distant stimulation from the primary tumor, BMDCs migrate from the bone marrow to organ sites and self-assemble into a pre-metastatic niche that hosts migrating tumor cells from the primary site. Thus, disruption of this niche or selective targeting the migratory tumor cells may inhibit metastatic spread. Using GFP+ BMDC9s from genetically engineered mice, we characterized the role that recruitment of BMDCs may play in breast cancer metastasis. We assessed the BMDC recruitment profile in lethally irradiated female nu/nu mice transplanted with GFP + BMDCs from donor mice, followed by orthotopic placement of MDA-MB-231/luc cells or injected with MDA-MB-231/luc conditioned media for 30 days. Flow cytometry results show a gradual increase in the recruitment of CD11b + VEGFR-1 + cells in all the tissues examined from tumor-bearing mice, particularly lungs and lymph nodes. Recruitment of these cells to the liver in mice treated only with MDA-MB-231/luc conditioned media was also apparent and at higher levels than to livers of mice with the orthotopically-placed tumors. Significant recruitment of CD11b + VEGFR-2 + BMDCs was observed to liver, lung and lymph nodes. Interestingly, MDA-MB-231/luc conditioned media appeared to recruit this subset of cells more strongly to liver and lung tissues than did signaling from orthotopic tumors, while spleen and lymph node showed less recruitment of CD11b + VEGFR-2 + BMDCs. Treatment with GrB/VEGF fusion construct - a novel granzyme B-based pro-apoptotic fusion protein which specifically targets cells harboring VEGFRs - indicated that GrB/VEGF normalized recruitment of VEGFR-1+ or VEFGR-2+ cells to lungs when assessed two weeks after the final treatment. GrB/VEGF treatment also increased recruitment of F4/80+ macrophages to the lung, including those with the CD11b+Gr-1- signature, which were otherwise significantly reduced. GrB/VEGF also impacted the BMDC profile of several cell lineages in the primary tumor. Studies are ongoing to understand the impact of GrB/VEGF systemic administration on lung metastasis. Identifying key players in modulating the formation of the pre-metastatic niche and the early development of metastasis will be critical in designing targeted therapeutic approaches to inhibit the metastatic process. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Khalid A. Mohamedali, Lawrence H. Cheung, Michael G. Rosenblum. Impacting early events in metastatic spread: Targeted therapeutics to disrupt formation of the pre-metastatic niche and development of lung metastases [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 4182.