Abstract 3615: Targeting tumor-brain crosstalk in invasive brain metastases

Abstract

Abstract Background: An estimated 20-40% of cancer patients develop brain metastases (BrM), mostly those affected by lung cancer, breast cancer or melanoma. Unfortunately, these patients suffer from poor outcomes and diminished quality of life. Few BrM treatment options beyond local therapy exist and this is often a short-term solution as 60% of resected BrM recur within 1 year. Our group discovered that patient prognosis is linked to BrM invasiveness, with highly invasive (HI) BrM more likely to recur, compared to minimally invasive (MI) BrM. This has presented us the opportunity to investigate exploitable biological mechanisms driving HI BrM. For instance, invasive signaling can be driven by microenvironmental proteins such as growth and immunological factors (cytokines) secreted by surrounding brain or cancer cells, through inter-cellular or self-feeding autocrine loops. Hypothesis: Considering the influence of secreted factors on cancer invasion and the brain microenvironment, I hypothesize that secretory profiling of BrM and brain parenchymal cells will be mechanistically insightful and help identify potential targetable drivers of BrM invasion. Results: To identify BrM invasion-related tumor- and brain-derived factors, I performed human- and mouse-specific high throughput Enzyme-Linked Immunosorbent Assay (ELISA)-based screens on conditioned media from mouse brain slices harboring intracranial MI or HI BrM patient-derived xenografts (PDX). This secretome screen reveals distinct MI and HI secretory profiles for melanoma, breast cancer and lung cancer BrMs and several HI BrM-derived factors of interest have been identified. Such factors are important to investigate as possible drivers of invasiveness in BrM through functional studies. Conclusion: BrM patients currently face a bleak prognosis, with few treatment options and a median survival of only 8-16 months. Considering the clinical availability of targeted therapies including inhibitors for growth factor-binding tyrosine kinases, antibody-drug conjugates, and immunotherapy, this project will help elucidate the cancer-brain crosstalk which may be exploited therapeutically with existing drugs in patients with frequently recurring HI BrM. ADDIN Citation Format: Caitlyn Mourcos, Sarah M. Maritan, Matthew G. Annis, Georgia Kruck, Alexander Nowakowski, Anna-Maria Lazaratos, Kevin Petrecca, Peter Siegel. Targeting tumor-brain crosstalk in invasive brain metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3615.