Prostate cancer is the most common cancer in American men and the second most common cause of cancer-related death. When prostate cancer becomes advanced, it will spread (metastasize) to several organs such as liver and brain. However, one location it favors for metastasis is the skeleton. Over 90' of men that die of prostate cancer or have advanced disease will have metastases in the bone. Unfortunately these bone metastases cause very severe and intractable pain due to the destruction of the bone. Additionally, they can cause compression of nerves and lead to fractures. Thus, understanding how the cancer cells grow in bone and affect the bone is very critical to the battle against prostate cancer because this knowledge may be used to identify targets to inhibit spread of prostate cancer to bone. To understand the interaction between prostate cancer and bone, we must first understand the biology of bone. The bone is a mineralized tissue. Two main cells play a role in the bone production and destruction. The osteoblast is the cell that produces bone mineral; whereas the osteoclast is the cell that resorbs the bone. When the osteoclast resorbs bone, the bone releases a variety of growth factors that stimulate prostate cancer growth. Additionally, as the osteoclasts resorb bone, this may make new space for the tumor to grow. Finally, the process of bone resorption is often associated with the pain felt by many patients with cancer in the bones. Thus, all these reasons suggest that inhibition of osteoclasts may diminish tumor growth and pain in bone.
Recently, a key regulator of osteoclast formation has been identified. Known as RANKL, this protein can be inhibited by another protein called osteoprotegerin (OPG). Our proposed work is based on an article we published last year (Zhang et al, J Clin Invest , 2001) in which we demonstrated that we could inhibit prostate tumor growth in the bone of mice by administering OPG. Thus, this publication provides the support for the concept that inhibiting osteoclast activity will diminish tumor growth in bone. However, OPG may favor the growth of tumor cells directly by inhibiting their cell death. Thus, in the current project, we are attacking this problem by two methods as described below: (1) We propose to determine how OPG levels are regulated in prostate cancer cells. If we know this, we may be able to modulate OPG levels in favor of inhibiting prostate cancer growth in bone. (2) We plan to evaluate two novel compounds that inhibit RANKL for their ability to inhibit development and progression of tumor growth in the bone of mice. If we are successful, these studies should provide the data needed to perform clinical trials with either one of these compounds. Such a trial may lead to real and timely advances to help combat this painful aspect of prostate cancer.