Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment

SIMPLE SUMMARY: Solid tumors such as prostate, breast, and lung cancers frequently spread to bone, causing severe pain, disability, and cancer-related deaths. The multiple types of non-cancerous cells in the bone interact with tumor cells to reduce the response to cancer therapies and promote further cancer growth. Studies of cellular interactions in this environment are needed in order to discover new therapies to treat and inhibit bone metastases. This review summarizes the current state of approaches used to study bone metastases, important pathways that could potentially be therapeutically targeted, and the status of clinical investigations of new drugs to treat bone metastases. ABSTRACT: Bone metastases represent a lethal condition that frequently occurs in solid tumors such as prostate, breast, lung, and renal cell carcinomas, and increase the risk of skeletal-related events (SREs) including pain, pathologic fractures, and spinal cord compression. This unique metastatic niche consists of a multicellular complex that cancer cells co-opt to engender bone remodeling, immune suppression, and stromal-mediated therapeutic resistance. This review comprehensively discusses clinical challenges of bone metastases, novel preclinical models of the bone and bone marrow microenviroment, and crucial signaling pathways active in bone homeostasis and metastatic niche. These studies establish the context to summarize the current state of investigational agents targeting BM, and approaches to improve BM-targeting therapies. Finally, we discuss opportunities to advance research in bone and bone marrow microenvironments by increasing complexity of humanized preclinical models and fostering interdisciplinary collaborations to translational research in this challenging metastatic niche.