TARGETS FOR BREAST CANCER BONE METASTASIS

Src

• Src activity regulates many pro-metastatic abilities of breast cancer cells and is also required for the generation of functional, bone-resorbing osteoclasts, making it an ideal candidate for therapeutic intervention for breast cancer bone metastasis.
• A Src-related gene expression signature has been identified in a subset of primary breast tumors and is highly predictive of the development of bone metastases. Several Src inhibitors are being tested in clinical trials, with many more in preclinical development.

TGF-β

• The TGF-β pathway is believed to exert opposing roles during cancer progression, acting as a growth inhibitor in normal epithelium and as a promoter of cancer invasiveness and metastasis as the disease progresses. Ample data exists to support both of these roles, and the diverse, often opposing effects, of TGF-β signaling on both cancer cells and cells within the tumor microenvironment make this a challenging pathway to target therapeutically. However, the large body of data pointing to the ability of this pathway to augment breast cancer metastasis will justify the continued development and testing of TGF-β inhibitors for use as anticancer agents.

Receptor activator of NF-κB ligand

• Receptor activator of NF-κB ligand (RANKL) is a critical mediator of osteoclast formation and is commonly deregulated during the process of breast cancer bone metastasis. Denosumab, a RANKL-neutralizing antibody, has demonstrated superior efficacy as an antiresorptive agent when compared with bisphosphonates. This agent is currently being investigated as an antibone metastatic therapy in PhaseIII clinical trials for patients with breast cancer or multiple myeloma.

Cathepsin K

• Cathepsin K is a proteolytic enzyme produced by osteoclasts, and contributes to the Collagen I degradation that occurs during bone resorption.
• Cathepsin K may facilitate breast cancer cell invasion.
• Odanacatib is a highly specific Cathepsin K inhibitor that is currently being investigated for its utility in treating numerous disorders that are characterized by excessive bone resorption.

CXCR4

• CXCR4 is a G-protein-coupled receptor commonly expressed in breast cancer cells that can facilitate the development of bone metastasis. It is also expressed by hematopoietic precursor cells and promotes their retention in the bone marrow.
• While CXCR4 inhibition may diminish the pro-metastatic abilities of breast cancer cells and promote the mobilization of hematopoietic precursor cells, it may also result in increased osteoclast activity. Thus, the effects of pharmacological CXCR4 inhibitors, such as plerixafor and CTCE-9908, should be investigated with respect to these undesirable effects on the promotion of bone resorption if they are to be used as antibone metastasis therapies.

Glycoprotein nonmetastatic B

• Glycoprotein nonmetastatic B (GPNMB) is a novel target expressed on the surface of breast cancer cells, which can promote bone metastasis in vivo. Its role in bone physiology is beginning to be elucidated and appears to be required for osteoblast and osteoclast function. CDX-011 is a GPNMB-targeted antibody drug conjugate that is yielding promising results in PhaseII trials for the treatment of metastatic breast cancer.

EGF-family ligands

• Recent data suggests that EGF initiated signaling can have profound effects on bone resident cells, including their ability to impair osteoblast differentiation and promote osteoclast formation. The net effect is to promote conditions that favor breast cancer induced osteolysis during the formation of breast cancer bone metastasis. A re-evaluation of therapeutic agents designed to impair EGFR signaling, which have displayed modest effects in treating primary breast cancer, may be warranted in the context of breast cancer metastasis to bone.