Grant: Operating Grant

Bone metastases are catastrophic consequences of breast cancer progression and are present in up to 70% of patients who die from breast cancer. Skeletal metastases cause considerable suffering due to high serum calcium, pathological fractures and intractable pain, and once metastases invade bone, they are usually fatal. Breast cancer easily spreads to the skeleton; tumor cells first escape the primary site in the breast, then migrate through the bloodstream and reach the bone marrow. There, they stimulate bone-destroying cells (osteoclasts) to create niches in the bone where the cancer cells can multiply and start the skeletal invasion. Breast cancer cells are known to overproduce a biochemical factor called parathyroid hormone-related protein (PTHrP) which stimulates the bone-resorption activity of osteoclasts, allowing the creation of a favorable environment for cancer invasion. PTHrP also promotes growth of the invading tumor cells, and is suspected of controlling the spread from the primary site to the metastasis area. Bone metastases are currently treated with bisphosphonates, a family of drugs that impair osteoclasts' bone-destroying capacity. Bisphosphonates are not a cure, however, and reduce bone complications in only 20% of patients. Importantly, bisphosphonates specifically target osteoclast activity, and do not address other aspects of bone metastasis such as tumor cell growth and spread from the primary site. Our recent results suggest that PTHrP may play a crucial role in these other aspects of skeletal metastasis. In order to improve the efficacy of the current therapy, this application proposes to examine the possibility of countering breast cancer metastatic spread through PTHrP inhibition in combination with bisphosphonate treatment. We will use a neutralizing anti-PTHrP antibody developed in our laboratory with the goal to create an enhanced therapy addressing additional aspects of metastatic spread to the skeleton.