Osteosarcoma is a particularly nasty form of cancer that affects both dogs and humans. The bone tumors it causes are extremely aggressive, frequently metastasize to other organs, and have a very high mortality rate. Even with treatment, the five year osteosarcoma survival rate in people is only 60 percent and the two year survival rate in dogs is even lower – a frightening 20 percent. New therapies for osteosarcoma are clearly needed, and so is a better way to test them.
With the help of the AKC Canine Health Foundation, Douglas H. Thamm and his colleagues from Colorado State University have been investigating the possible role of a protein known as survivin in the treatment of osteosarcoma. Survivin is found in both dogs and humans, and it has two known functions – regulating cell division and inhibiting apoptosis, a process that is also known as programmed cell death. As survivin is critical for the growth and survival of cancer cells, but normal cells can do just fine without it, there has been a growing interest in whether inhibiting its production might be a useful method of osteosarcoma treatment.
As part of a study published in the journal Cancer Research, the scientists investigated what would happen if they used a molecule known as a small interfering RNA (siRNA) to interrupt the production of survivin in tumor cells. The siRNA was designed to bind to the segments of cellular RNA that code for survivin and prevent them from being transcribed into functional protein. They hoped that, by limiting survivin production, the siRNA treatment could reduce tumor growth and increase the cancer cells’ susceptibility to chemotherapy regimens.
The experiments were a success. Osteosarcoma cell lines that were treated with siRNA expressed approximately 80 percent less survivin than control cells and cells which received a sham treatment. Treated cells also divided less often, were more likely to die from apoptosis, and had increased susceptibility to chemotherapy with doxorubicin and carboplatin.
Dr. Thamm and colleagues also examined whether survivin levels in tumor cells were correlated to the length of survival for dogs diagnosed with osteosarcoma. They found that dogs with lower levels of survivin lived almost twice as long after diagnosis as dogs with higher levels of the protein. Furthermore, survivin levels were highly correlated with histological cancer grade, similar to what had been seen in humans.
The fact that this research confirmed that survivin is a useful target for osteosarcoma treatment is extremely exciting, as early clinical trials of anti-survivin vaccines are currently underway. Even more important, however, may be the confirmation that survivin is as closely related to osteosarcoma prognosis in dogs as it is in humans. This means that canine osteosarcomas can be used as a model for human disease, something which will hopefully be useful in the search for effective treatments in both species.
It may turn out that, in the end, surviving osteosarcoma is a matter of stopping survivin.
This work was funded in part by AKC Canine Health Foundation grant 1064-A.