Targeted Agents in Preclinical and Early Clinical Development for the Treatment of Cancer Bone Metastases

ABSTRACT

Introduction: Bone is one of the preferential organs affected in patients with metastatic cancers. Bone metastases contribute substantially to morbidity and mortality in cancer patients, especially for those with breast and prostate cancer. Bisphosphonates and denosumab, potent inhibitors of osteoclastic bone resorption, are the current standard of care for bone metastases; however, their effects are palliative. Recent preclinical studies have revealed a variety of potential targets for the development of novel therapeutic agents. Some of these are currently being evaluated in clinical trials.

Areas covered: This paper reviews the preclinical and early clinical development of molecularly targeted agents for the treatment of bone metastases. The agents are categorized according to their targets, osteoclasts, osteoblasts, metastatic cancer cells, and the bone microenvironment.

Expert opinion: Recent advances in our understanding of the molecular and cellular mechanisms of bone metastases have led to the development of novel therapeutic options. Although most of their effects have yet to be proved in clinical studies, it is the author’s belief that they will contribute significantly to improving the treatment outcome of patients with bone metastases in the near future.

KEYWORDS:

• bone metastasis
• bone microenvironment
• cancer
• clinical development
• osteoblasts
• osteoclasts

Article highlights

• Bone is one of the preferential target sites of cancer metastases.

• Bisphosphonates and denosumab are the current standard of care for bone metastases; however, their effects are palliative. Bone metastases are generally incurable with currently available therapeutic options.

• In the development of bone metastases, the interaction between metastatic cancer cells and the bone microenvironment plays critical roles. The ‘vicious cycle’ theory is widely accepted to explain their crosstalk. All of the cells and molecules involved in this theory are potential therapeutic targets.

• Recent advances in our understanding of the mechanisms of bone metastases have led to the development of novel therapeutic agents, and some of these are currently undergoing clinical trials in patients with bone metastases.

• Emerging molecularly targeted agents will contribute significantly to improve the treatment outcome of patients with bone metastases in the near future.

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Financial & Competing Interests Disclosure

T Hiraga is supported by funds from the Japan Society for the Promotion of Science (JSPS) <KAKENHI> (grant number 15K11093) and the Naito Foundation. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.