Abstract
Simple SummarySolid 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.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.
Highlights
Within solid tumors, prostate and breast carcinomas have greater tropism for bone, involved in up to 80–90% of patients with metastatic disease [1]
Non-small cell lung cancer (NSCLC) with ALK rearrangements showed a higher frequency of sclerotic bone lesions compared to non-small cell lung cancer (NSCLC) with EGFR-activating mutations, or NSCLC lacking either of these targetable alterations [4]
In mouse BC xenografts, knockdown of BMPR1a in BC cell lines suppressed RANKL production, inhibited cancer-induced osteoclastogenesis, and reduced osteolytic metastases [244]. These results suggest that bone morphogenic protein (BMP) are potential targets to prevent BM, though potential therapies must be tailored to specific BMP molecules and metastatic cellular contexts
Summary
Prostate and breast carcinomas have greater tropism for bone, involved in up to 80–90% of patients with metastatic disease [1]. Bone and bone marrow represent distinct niches compared to other sites in patients with metastatic solid tumors; there is limited clinical data on bone responses. This is due, in part, to challenges in obtaining and processing BM from patients and difficulty assessing radiographic responses in bone. Agents that prevent bone resorption include zoledronic acid, a bisphosphonate that inhibits the production of RANK-ligand (RANKL) and stimulates synthesis of osteoprotegerin (OPG), and denosumab, an antibody that inhibits the osteoclast-promoter RANKL [98,99,100,101] These agents have minimal effect on overall survival, but prevent and delay SREs. Focused external beam radiation therapy is effective in palliating pain and can prevent further progression at the sites of irradiation. Advances in systemic treatment of BM are acutely needed
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
