If cancer spreads to the bones, it can be particularly difficult to treat.
The majority of cancer deaths are not due to the initial tumor; they are due to secondary tumors that develop in other parts of the body. These are called metastases.
Sometimes, cancer enters bones. In fact, in late stage breast cancer, approximately 70 percent of patients experience bone metastasis. This increases the risk of bone pain, fractures, and other life-threatening events.
Once cancer has put down roots in bone, it can be very difficult to combat. Current treatments do not work particularly well; they come with a range of undesirable side effects and the cancer can become resistant to them.
Investigating bone metastasis
A great deal of research time has been spent trying to understand just how cancer spreads, how it sets up shop in other tissues, and how it can be stopped or slowed. Yibin Kang and his team of researchers at Princeton University in New Jersey are involved in this effort.
Lead study author Hanqiu Zheng, former postdoctoral fellow with Kang, explains the team’s focus, saying, “The Kang Lab primarily studies breast cancer metastasis — how cancer cells spread from the breast to other organs — because what kills the vast majority of cancer patients is not the original tumor but rather metastasis.”
Their recent study focused specifically on bone metastases and how cancer cells communicate with bone cells.
Rebecca Tang, also in Kang’s team, explains, “Previous work in the lab had shown that a molecule called Jagged1 is a critical part of this crosstalk and makes it easier for breast cancer cells to metastasize to bone.”
“We, therefore, wanted to see if we could prevent or reduce metastasis by using an antibody called 15D11 to block Jagged1,” she adds.
Their results were published this month in the journal Cancer Cell.
Studying cancer to bone communication
In healthy bones, there is a constant ebb and flow: bone is removed by osteoclasts and rebuilt by osteoblasts. This constant regeneration means that bone tissue is always healthy and fully functioning.
But in bone cancer, this normal process is hijacked. Osteoclasts can be tricked into destroying too much bone, or osteoblasts may be cajoled into sheltering tumor cells and protecting them from chemotherapy. The recent investigation was particularly interested in the molecular role of osteoblasts in bone metastasis.
“Tumors are essentially hiding in the cradles of the osteoblasts,” says Kang.
They discovered that when 15D11 was given alongside chemotherapy, it worked better than either treatment on its own. Interestingly, the team had first thought that the antibody would only work against tumors with a high expression of Jagged1, but even those with low Jagged1 expression were reduced.
Standard chemotherapy usually stops working when Jagged1 starts being made by osteoblasts; the tumor effectively uses Jagged1 as a shield. By specifically targeting Jagged1, 15D11 destroys this shield and chemotherapy can continue working.
Jagged1 in a mouse model
To further investigate this relationship, Kang and his team used a genetically engineered mouse model that expresses Jagged1 in bone cells. This strain is particularly sensitive to the growth of breast cancer in their bones.
Experiments with the mice backed up the initial findings: mice that were treated with both 15D11 and chemotherapy fared better than those given either treatment alone. In one experiment, the bone tumor was reduced more than 100-fold after receiving both drugs.
“This is a remarkable response that we have never observed in any of our previous tests of therapeutic agents against bone metastasis in mice.”
Although this study only investigated breast cancer within bone, the researchers believe that this method could work for other types of cancer that metastasize to bone, such as prostate cancer.
The next step will be to take this research to human trials. Kang hopes that this will be a relatively quick process because 15D11 is “fully human,” having been generated in a “humanized mouse.”
Due to the fact that bone metastases are so difficult to treat, any new drug targets or interventions are gratefully received. Hopefully, in the not too distant future, 15D11 will enter the ranks in the fight against cancer.
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