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Advance in Blocking Bone Cancer Pain Aims for Pain Relief Without Sedation

MINNEAPOLIS / ST. PAUL--In a study that advances the fight against bone cancer pain affecting millions of people, University of Minnesota scientists have identified and disabled the cell that is chiefly responsible for causing this pain. The study in animal models is reported in the May issue of Nature Medicine and was funded by the National Institutes of Health and the Department of Veterans Affairs. The treatment has not yet been tested in human patients.

      Most cases of bone cancer occur as the result of cancer cells spreading from other parts of the body, most commonly from the prostate, breast, and lung. In the United States, one in six men will develop prostate cancer. In about half of all these cases, the cancer will metastasize throughout the skeletal structure of the victim. Between 75 and 90 percent of patients with this advanced cancer will experience significant life-altering, cancer-induced pain. Current therapies for treating this type of pain can have negative side effects such as sedation, impaired cognitive function and severe constipation, said team leader Patrick Mantyh, a neuroscientist at the university and a research scientist at the Veterans Affairs Medical Center in Minneapolis.

      Ironically, said Mantyh, advances in medicine have in some ways made the problem worse. While recent treatment improvements have prolonged patients' lives, there have been no matched advances in therapies for the bone pain. As a result, patients may gain longer lifespan but with a diminished quality of life.

      "What is perhaps most unique is our approach to the problem," said Mantyh. "Instead of 'treating the symptom' of pain with analgesic therapies, we are targeting the very cells we have identified as the cause of the pain itself."

       Last year Mantyh's team began working with Denis Clohisy, an orthopedic oncology surgeon at the university, to create the first animal model for the study of bone cancer pain. Using this model, the scientists identified a direct correlation between cancer-induced bone destruction and pain; the two phenomena seemed to develop in tandem. The team then focused on the cause of the bone destruction and the biological mechanism of the pain.

      In healthy bone, two groups of specialized cells work together to continuously replace old bone tissue with new bone tissue. The first group of cells (osteoclasts) basically dissolve and remove bone tissue while the other group (osteoblasts) produce new cells and replenish the bone tissue.

      The scientists observed that when cancer is present in bone, secretions from the tumor cells cause the osteoclasts to shift into high gear, so bone is destroyed more rapidly than it can be replenished. The changes in the bone were accompanied by a significant neurochemical change in the area of the spinal cord that sends pain signals to the brain. This change was matched an increase in pain behaviour in the study subjects. The results suggested that accelerated osteoclastic activity is directly responsible for bone cancer pain.

      Mantyh and Clohisy figured that by stopping the osteoclastic activity in the bone they might halt the chemical changes in the spinal cord. Several substances are effective in blocking osteoclastic activity. In deciding which substance to use, the researchers sought one that would both block the osteoclasts and offer a clear understanding of the mechanism by which it did so.

       The team chose a naturally occurring substance, osteoprotegerin (OPG), as the most qualified candidate on both counts.

      "In our approach, we aren't satisfied to know that it works, we need to know how it works," said Mantyh.

      Over several months of testing, OPG was shown to rapidly block osteoclastic activity in the animal models. Most significantly, said Mantyh, the chemical changes in the spinal cord that are thought to amplify pain signals from the cancerous bone were also blocked, as were the pain-related behaviors. The results suggested that OPG, or drugs with similar activity, may provide an effective remedy for bone cancer pain.

     "The immediate objective of the team is to develop new and more effective therapies that block chronic pain without adverse side effects," Mantyh said. "When one relieves chronic pain, one dramatically improves the quality of life and truly returns the life to the patient. That is the ultimate goal of our work here."

Mantyh and Clohisy are members of the University of Minnesota's Cancer Center. Mantyh works in the departments of preventive sciences, neuroscience and psychiatry. Clohisy holds the Roby C. Thompson, Jr. Chair in Musculoskeletal Oncology and works in the department of orthopaedic surgery.

                                                                                                   

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