Novel Bone-Targeting Agents in Prostate Cancer
Prostate cancer (PC) is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death among American men. Bone is by far the most common site for metastasis. The median survival of patients from the development of bone metastases is ~3 years. During this period, patients are at increased risk of skeletal-related events (SREs) including: intractable bone pain, pathological fractures and spinal-cord compression. Several novel bone-targeted agents including bisphosphonates, receptor activator of nuclear factor κB (RANK) ligand monoclonal antibodies, endothelin receptor antagonists, bone-seeking radioisotopes, selective estrogen receptor (ER) modulators and tyrosine kinase inhibitors are now available and under evaluation in clinical trials in PC patients with bone metastases. This review article will provide an overview of the multiple emerging novel bone-targeted therapies in PC.
Prostate cancer (PC) is the most commonly diagnosed solid organ cancer and the second leading cause of cancer death among men in the United States. Bone metastases are a hallmark of advanced PC. Approximately 80–90% of men with advanced cancer will develop bone metastases. PC-related morbidity and mortality are closely associated with the formation of metastases. The median survival of patients' approaches 3 years after the onset of bone metastases. Although bone metastases in PC are predominantly osteoblastic, bone resorption also is increased. Tumor cells stimulate both osteoclasts and osteoblasts through the local release of paracrine factors including: parathyroid hormone-related protein, receptor activator of NF-κB ligand (RANKL), macrophage inflammatory protein-1-α, interleukin-1 and interleukin-6. Within the same tumor-stroma microenvironments, bone marrow stromal cells express the mRNA of factors needed for osteoclast generation, such as RANKL. RANKL reacts with the receptor activator of nuclear factor κB (RANK) to promote the generation of osteoclasts.
In the normal bone microenvironment, an equal balance of new bone matrix formation and old bone matrix resorption is achieved via the coordinated activity of bone-degrading osteoclasts and bone-forming osteoblasts. Osteoprotegerin helps maintain this balance. Osteoprotegerin is an RANK homolog that works by binding to RANKL on osteoblast/stromal cells, thereby blocking the RANKL–RANK interaction between osteoblast/stromal cells and osteoclast precursors. However, in metastatic bone disease the normal balance of bone resorption and formation is disrupted by a complex network of multiple soluble factors, signaling pathways and transcriptional regulators that increase RANKL signaling, which upsets this balance (Figure 1). The resulting excess osteoclast activity leads to bone loss and increases fracture risk.
(Enlarge Image)
Figure 1.
An overview of the vicious circle of bone destruction and tumor growth in osteolytic metastases. OPG, osteoprotegerin; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor-κB ligand. Adapted from Boyle et al.
Treatment with bisphosphonates is a currently accepted standard for PC patients with bone metastases. Bisphosphonates such as zoledronic acid (ZA) are deposited into the bone matrix, and thereby protect against the detrimental effects of activated osteoclasts, maintain bone strength and decrease skeletal-related events (SREs). Several novel bone-targeted agents including denosumab, atrasentan, zibotentan, toremifene and most recently Radium-223 have emerged and have been tested in clinical trials. In light of the rapidly expanding number of bone-targeting agents currently in clinical development, we have summarized in this review the rationale and clinical data behind each novel agent.
Abstract and Introduction
Abstract
Prostate cancer (PC) is the most commonly diagnosed non-skin cancer and the second leading cause of cancer death among American men. Bone is by far the most common site for metastasis. The median survival of patients from the development of bone metastases is ~3 years. During this period, patients are at increased risk of skeletal-related events (SREs) including: intractable bone pain, pathological fractures and spinal-cord compression. Several novel bone-targeted agents including bisphosphonates, receptor activator of nuclear factor κB (RANK) ligand monoclonal antibodies, endothelin receptor antagonists, bone-seeking radioisotopes, selective estrogen receptor (ER) modulators and tyrosine kinase inhibitors are now available and under evaluation in clinical trials in PC patients with bone metastases. This review article will provide an overview of the multiple emerging novel bone-targeted therapies in PC.
Introduction
Prostate cancer (PC) is the most commonly diagnosed solid organ cancer and the second leading cause of cancer death among men in the United States. Bone metastases are a hallmark of advanced PC. Approximately 80–90% of men with advanced cancer will develop bone metastases. PC-related morbidity and mortality are closely associated with the formation of metastases. The median survival of patients' approaches 3 years after the onset of bone metastases. Although bone metastases in PC are predominantly osteoblastic, bone resorption also is increased. Tumor cells stimulate both osteoclasts and osteoblasts through the local release of paracrine factors including: parathyroid hormone-related protein, receptor activator of NF-κB ligand (RANKL), macrophage inflammatory protein-1-α, interleukin-1 and interleukin-6. Within the same tumor-stroma microenvironments, bone marrow stromal cells express the mRNA of factors needed for osteoclast generation, such as RANKL. RANKL reacts with the receptor activator of nuclear factor κB (RANK) to promote the generation of osteoclasts.
In the normal bone microenvironment, an equal balance of new bone matrix formation and old bone matrix resorption is achieved via the coordinated activity of bone-degrading osteoclasts and bone-forming osteoblasts. Osteoprotegerin helps maintain this balance. Osteoprotegerin is an RANK homolog that works by binding to RANKL on osteoblast/stromal cells, thereby blocking the RANKL–RANK interaction between osteoblast/stromal cells and osteoclast precursors. However, in metastatic bone disease the normal balance of bone resorption and formation is disrupted by a complex network of multiple soluble factors, signaling pathways and transcriptional regulators that increase RANKL signaling, which upsets this balance (Figure 1). The resulting excess osteoclast activity leads to bone loss and increases fracture risk.
(Enlarge Image)
Figure 1.
An overview of the vicious circle of bone destruction and tumor growth in osteolytic metastases. OPG, osteoprotegerin; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor-κB ligand. Adapted from Boyle et al.
Treatment with bisphosphonates is a currently accepted standard for PC patients with bone metastases. Bisphosphonates such as zoledronic acid (ZA) are deposited into the bone matrix, and thereby protect against the detrimental effects of activated osteoclasts, maintain bone strength and decrease skeletal-related events (SREs). Several novel bone-targeted agents including denosumab, atrasentan, zibotentan, toremifene and most recently Radium-223 have emerged and have been tested in clinical trials. In light of the rapidly expanding number of bone-targeting agents currently in clinical development, we have summarized in this review the rationale and clinical data behind each novel agent.