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Among them are children with spondylocostal dysostosis, a rare disease in which babies are born with fused and misshapen vertebrae and a rib cage several sizes too small. Children who survive often can’t breathe without a ventilator and sometimes need a hole inserted in their trachea, or major rib and chest surgery, just to breathe. “It tugs at your heartstrings,” Lee says. “Their brain is okay, but they’re kind of trapped in a body.”
Lee noticed that many patients with spondylocostal dysostosis weren’t growing. What’s more, their bones were “washed-out” or darker on x-rays, which suggested they had low bone mass—an observation that Lee corroborated with bone density scans. Lee knew that genes in a signaling pathway known as Notch were mutated in this disease and that Notch signaling helped immature stem cells in the bone marrow decide which of two types of blood cells to become. He suspected that Notch might help another type of bone marrow stem cell decide whether to become a bone- or cartilage-forming cell.
We’re very excited because we’ve got what we think is a more authentic model of osteosarcoma,” Lee says.
Sure enough, his lab group discovered, it did. Mice with overactive Notch in their bone marrow stem cells developed far too much bone in their skull, ribs, and leg bones, the team reported in Nature Medicine in 2008. But it was immature bone, not the strong, layered bone that supports the healthy adult skeleton. Lots of immature bone forms in human osteosarcoma, too. That “helped us make the leap to bone cancer,” Lee says.
To see if Notch signaling was also altered in bone cancer, Lee’s group tested lab-grown human bone cancer cells, including tissue cultured directly from patients’ bone tumors. As anticipated, Notch signaling was overactive, suggesting that the pathway contributed to human osteosarcoma. And compounds that block Notch signaling dramatically slowed the growth of human tumors implanted in immune-deficient mice, the group reported in Human Molecular Genetics in 2009.
Since then, the researchers have engineered a line of mice with an intact immune system that would be better than immune-deficient mice at predicting how potential drug compounds might affect tumors in people, Lee says. Notch is activated continually in these mice, and the animals develop bone cancer, Lee’s team reported last October at the American Society for Bone and Mineral Research. “We’re very excited because we’ve got what we think is a more authentic model of osteosarcoma,” Lee says.
Now they’re testing whether blocking Notch genetically in mice will prevent bone cancer. If so, then compounds that block Notch signaling could also stop the disease. And if that works in mice, Lee plans to test them on osteosarcoma patients.
As with other bone diseases, treating bone cancer is also a matter of regaining balance. Lee thinks it’s possible: “If we could inhibit Notch in osteosarcoma, that would be spectacular.” New drugs for bone cancers, childhood skeletal diseases, fracture healing, and a major disease of aging may all come from these pathway explorations.