The pain of bone cancer can be especially intense, and it's often the most difficult cancer pain to treat because it goes to so many areas of the body. To give patients relief, physicians have relied on the tools at hand: usually prescribing drugs—opiates, for example—that work for other kinds of pain. The problem is that the side effects of these drugs can be as debilitating as the pain.

Masonic Cancer Center member Patrick Mantyh, Ph.D., believes he has found a better approach to treat bone cancer pain. A laboratory scientist, Mantyh is a member of the Masonic Cancer Center's research program on cancer progression and metastasis, and one of the leading basic researchers in the United States on bone cancer pain. His years of research, often done in collaboration with Cancer Center member Denis Clohisy, M.D., have resulted in the finding of a promising new approach to the problem. It's based on the molecular mechanics of pain and the biology of how pain works.

Says Mantyh: "Opiates are fantastic drugs for the control and relief of pain but they come with side effects such as constipation, drowsiness, nausea, and breathing difficulty. Finding new analgesics is critical because more and more patients with many types of cancer are living longer with cancer as a chronic disease. It's important to make their lives as comfortable and normal as possible.

"Patients can get their lives back if you relieve the pain."

Building better tools against pain

The goal of Mantyh's laboratory research is to develop a mechanism-based therapy specifically for bone cancer, and not just to use something that exists for headache or muscle pain. He created the first animal model for studying, identifying, and disabling the cells responsible for causing bone cancer pain. In 1999, he delivered his first research paper on blocking the pain of bone cancer. Now his research team, along with Clohisy's, is creating a totally new set of "tools" based on an understanding of how pain works at the molecular level. (See related article, "Meeting of the minds," for information about Clohisy's clinical research on sarcoma.)

Mantyh explains: "A substance called nerve growth factor (NGF) is what stimulates bone cancer pain by binding to sensory neurons. Scientists used to think that when tumor cells invaded a site, those cells released NGF. It has since been learned that the real culprits are the inflammatory and immune cells (known as tumor-associated macrophages) that the body sends to attack the cancer. They release NGF, which induces nerve fibers to sprout in the area of the bone where cancer has taken root. NGF also causes the nerve fibers to become overactive and highly sensitized."

"Finding new analgesics is critical because more and more patients with many types of cancer are living longer with cancer as a chronic disease. It's important to make their lives as comfortable and normal as possible. Patients can get their lives back if you relieve the pain."
— Patrick Mantyh, Ph.D.

With mice as test subjects, Mantyh's team has conducted several studies in which they injected an anti-NGF antibody at the site of the cancer. The research, funded by the National Institutes of Health (NIH) and the Veterans Administration (VA), started with sarcoma, which is a cancer of the bone or muscle. The antibody prevented NGF from binding to nerve cells in the bone. They found that anti-NGF was highly effective in reducing both early- and latestage bone cancer pain. And, the reduction was greater than that achieved with the use of morphine sulfate (a pain-relieving opiate) and with none of the side effects.

But would the anti-NGF work as effectively with other types of bone cancer, such as those that result when cancer spreads to bone from breast or prostate tumors? Mantyh and his colleagues conducted similar studies in breast- and prostate-induced bone cancers and found the same effect: significantly reduced pain.

These promising results have led to more studies for cancer and other painful conditions. Rinat Neuroscience, the Palo Alto, Calif. firm that produces the anti-NGF antibody, is now conducting clinical trials on humans to test the anti-NGF in prevention of osteoarthritis pain.

The next step for Mantyh is to investigate whether the compound has the potential to reduce the cancer as well as the pain.

Beyond the bone

Mantyh came to the University of Minnesota from UCLA in 1988 and in the past decade has solidified his reputation in the field of pain study with papers published in leading research journals: Science, PNAS, Nature, Nature Biotechnology, and Nature Medicine. Last year he published an article in the journal Cancer Research about his most recent findings — that anti-NGF therapy may be effective in reducing pain and enhancing the quality of life in patients with prostate tumor-induced bone cancer pain. He also recently received a Javits Merit Award from NIH and the Frederick Kerr Award in Basic Neuroscience Research from the American Pain Society.

Mantyh sees the University of Minnesota as the perfect place to conduct his research. In addition to his work at the Masonic Cancer Center, he directs the University of Minnesota's Neurosystems Center and is a professor in the Department of Diagnostic and Biological Sciences, Neuroscience and Psychiatry. Plus, he directs the Molecular Neurobiology Laboratory at the VA Medical Center in Minneapolis. These appointments across so many specialty areas afford him a full-spectrum view of what the cancer patient experiences.

"This is an applied translational effort directly aimed at helping the patient," he says. "But it also has immense benefits for furthering basic research understanding about pain.

"About two-thirds of new agents found in the laboratory, such the anti-NGF compound, fail," he says. "But why do they fail is the question. Being able to work with people in these other disciplines allows greater insight into basic biology and a greater understanding of the pain state."

Knowing more about bone cancer pain and finding better ways to treat it requires breaking down old patterns and methods to look at the problem in a new way, says Mantyh. He attributes many of the advances made by him and his team to the University students who work with him and the other experienced researchers in his laboratory.

"They have immense energy and enthusiasm that makes all of this possible," he says of his laboratory. He believes the students who work with him will use their experience in his laboratory as a platform for their own future cancer research.

"They'll take this vision and enthusiasm with them and I believe they'll have an impact far beyond our current investigations and for greater benefit of people with cancer," he says.

Mantyh conducts his research on bone cancer pain through the Masonic Cancer Center's Cancer Progression and Metastasis Research Program, which is led by James McCarthy, Ph.D. Team members who worked with Mantyh on the research described in this article include Joseph Ghilardi, senior scientist, and Kyle Halvorson and Molly Sevcik, both students. Grants from the National Institutes of Health and a Veteran's Administration Merit Review funded this research.

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This article was originally published in the Masonic Cancer Center 2006 Annual Report (PDF).