Antibody May Provide a Strategy Against Metastatic Bone Cancer

An antibody drug that targets part of the bone growth pathway can slow the growth of human osteosarcoma implanted in mice and prevent the tumor from spreading to other parts of the body, according to a study led by Johns Hopkins Kimmel Cancer Center scientists.

Osteosarcoma is one of the most common bone tumors affecting children and adolescents. It is usually treated with surgery and chemotherapy, but the disease spreads in between 25 and 40 percent of patients, and 75 percent of those patients will die of their disease.

These survival rates remain “mostly unchanged” since the 1980s, making it important to uncover new therapeutic options, says David M. Loeb, M.D., Ph.D., an associate professor of oncology and pediatrics and director of the Musculoskeletal Tumor Program at the Kimmel Cancer Center.

As Loeb and colleagues reported earlier this year in Oncotarget, the antibody targets a molecule called DKK-1, which may promote tumor growth in osteosarcoma. DKK-1 blocks part of the Wnt molecular signaling pathway that is key to normal bone development.

Loeb and colleagues implanted tumors grown from human osteosarcoma cells into mice and were able to detect human DKK-1 circulating in the blood shortly afterward. The higher the levels of DKK-1, the faster the tumors grew in the mice, the researchers found. When DKK-1 levels in the mice were high, during the first six weeks of tumor growth, tumors increased in volume at a rate of almost 1 percent every three days, while the rate later slowed to .35 percent when DKK-1 levels were low.

When the mice were treated with a DKK-1 antibody, their human DKK-1 levels became undetectable, and they experienced a substantial slowdown in tumor growth — a .47 percent volume increase every three days, compared to a .95 percent increase in untreated mice.

The researchers then studied the antibody’s effects on metastasis using a mouse model that Loeb and his colleagues developed to more closely mimic osteosarcoma treatment in young patients. They implanted the tumor in a leg bone in the mice, waited for the tumor to grow before doing surgery or amputation to remove the tumor, and then watched to see if the cancer would metastasize.

Only one of 24 mice treated with the DKK-1 antibody developed metastatic disease, compared to six of 18 mice that did not receive the antibody. The one mouse that developed a metastasis appeared to have a local recurrence of its cancer, suggesting that the original surgery to remove the tumor was not completely successful.

“The major limitation to treating patients with osteosarcoma is prevention of metastasis, and I think our major finding is that in the mice who had a good surgery — meaning no local relapse — none of the [antibody]-treated animals developed metastasis,” says Loeb. “I would want to give this to patients early on in their treatment but continue throughout treatment and even up to a year after chemotherapy ended to maximize our chance of preventing metastasis.”

The antibody drug used in the study, called BHQ880 and manufactured by Novartis, also has been tested in clinical trials for the treatment of multiple myeloma. Novartis has discontinued the drug, but Loeb says that comparable antibody drugs could be developed.

It is also possible, Loeb says, that there may be other therapeutic targets to be discovered within the Wnt signaling pathway. “I think we’ve only scratched the surface in terms of understanding how Wnt signaling affects osteosarcoma,” he says.

Other scientists who contributed to the research include Johns Hopkins researchers Seth D. Goldstein, Wendy Bautista Guzman and Masanori Hayashi and Matteo Trucco of the University of Miami Sylvester Cancer Center.

Funding for the study was provided by the National Cancer Institute (1R01CA138212-01, 2P30CA006973), the Pablove Foundation and the Giant Food Children’s Cancer Research Fund.