The Dilemma Of Targeting NFκB For The Treatment Of Secondary Cancer In Bone
The skeleton is a common site for metastatic cancer cells originated in distant organs. Skeletal-related events such as excessive bone damage and bone pain are often diagnosed in cancer patients suffering from bone metastasis and those undergoing cancer treatments such as chemotherapy. Once in bone, metastatic cancer cells acquire “bony” characteristics that enable these foreign cells to survive the harsh environment in the bone marrow and disrupt normal bone remodeling – a process by which old bone is removed and new bone is formed.
Bony cancer cells produce a plethora of factors that influence the differentiation and function of cells of the tumor microenvironment, particularly osteoclasts (bone-destroying cells) and osteoblasts (bone forming cells). Many of the factors produced by metastatic cancer cells in bone directly or indirectly activate inflammatory signaling pathways in local healthy cells present in the tumor microenvironment. One of these pathways is NFκB.
NFκB plays a key role in the regulation of bone growth in health and disease. Numerous studies have shown that genetic depletion of key components of this pathway in mice increased bone volume by reducing the number of osteoclasts and increasing the differentiation and maturation of osteoblasts. More recently, we and others have shown that treatment of osteoporotic (brittle bone) mice with NFκB inhibitors protected against bone loss by inhibition of osteoclasts.
Disrupting Bone – Cancer Cell Crosstalk By NFκB Inhibition
Since the publication of a paper in 2007 that reported that NFκB is implicated in the metastasis of breast cancer cells to bone, interest in NFκB as an attractive, druggable target for cancer-associated bone disease has been growing within the bone research community. Follow up work by our group in this area has shown that NFκB inhibitors reduced breast cancer-induced bone loss and inhibited breast cancer cell growth in bone.
In a recent study, we focused our investigation on the effects NFκB inhibition on osteoblasts and their ability to differentiate, influence the osteoclasts and to form new bone in the presence of cancer cells. Our results revealed that inhibition of NFκB in osteoblasts not only reduced their ability to support osteoclast formation and to cause bone destruction, but it also enhanced their maturation and reversed their growth inhibition by breast cancer cells and their derived factors.
The treatment of secondary breast cancer in bone is based on drugs that reduce bone loss by killing the osteoclasts. Whilst anti-osteoclast such as Bisphosphonates and Denosumab have been effective in the reduction of skeletal complications associated with various cancers, these agents have no significant, direct impact on bone formation. Our recent findings raise the possibility that NFκB inhibitors, as both pro-osteoblasts and anti-osteoclasts, may have an advantage over conventional anti-osteoclasts agents in the treatment of secondary breast cancer in bone.
Understanding The Danger Of Manipulating Osteoblasts In Cancer
The topic of targeting osteoblasts to treat secondary cancer in bone remains controversial, with researchers in the bone community expressing opposing views about its effectiveness.
Most researchers in the field would agree that enhancing osteoblast differentiation by NFκB inhibition would indeed encourage bone formation. However, the fact that osteoblasts are also responsible for osteoclast formation suggests that increasing their number in the tumor microenvironment may indirectly stimulate osteoclast formation and this, in turn, causes excessive bone damage. If proven, this will limit the usefulness of NFκB inhibitors for the treatment of secondary cancer in bone.
Optimists, myself included, are keeping an open mind. We believe that the role of NFκB activity in the crosstalk between cancer cells, osteoblasts, and osteoclasts merits future investigation. We, at my laboratory at the University of Sheffield, are currently carrying out additional experiments that evaluate the consequences and implications of osteoblast stimulation by NFκB inhibitors in preclinical models of metastatic cancer.
Such studies will open new opportunities to develop NFκB inhibitors that – alone or in combination with chemotherapy in a staged and timed treatment regime – may be of value in the management of cancer-associated bone disease and bone pain.