Scaling the Mountains behind the Mountains in Neuroblastoma Research

Great strides have been made in the treatment of neuroblastoma, a rare cancer of nerve tissue that usually occurs in children and most commonly arises in the adrenal gland. An array of therapies has been effective in slowing or stopping the disease — even when it spreads to lymph nodes, bone, and bone marrow — and increasing chances of survival.

With this success, however, a new problem has emerged. In some children, neuroblastomas that were brought under control later spread, or metastasize, to the brain. This devastating development is poorly understood, as researchers don’t understand how this metastasis occurs.

“This is a problem we did not anticipate because in the past we were focusing on controlling the disease elsewhere in the body,” says pediatric oncologist Nai-Kong Cheung, who heads Memorial Sloan Kettering’s Neuroblastoma Program. “It is like another mountain to scale behind the first mountain.”

Now a research team led by Dr. Cheung has identified common genetic alterations in advanced neuroblastomas that may help doctors predict the likelihood that the initial tumor will later recur in the brain. If the effect of these alterations is confirmed in experiments, it could guide the development of therapies to prevent the brain metastases.

Copying Errors

The researchers made their discovery by analyzing tumor samples taken from Memorial Sloan Kettering patients with neuroblastoma brain metastases. They studied the genetic makeup of 19 primary tumors and 27 metastatic tumors in the brain, including 12 “paired samples” — one of each type from the same person.

Specifically, they looked for copy number alterations (CNAs) in the DNA of cancer cells that were present both at diagnosis and when the cells metastasized to the brain. CNAs are differences in genetic sequence that arise when segments of DNA are duplicated or deleted during cell division. The researchers were able to identify specific CNA profiles that were present in metastatic tumors as well as in their corresponding paired primary tumors.

“These alterations were found more frequently than expected by chance in the samples we analyzed,” Dr. Cheung says. “These preexisting CNAs present at diagnosis might be useful in the future for predicting the likelihood of CNS metastasis. What remains unclear is whether these CNAs alone are sufficient to cause metastasis — that will need to be proven in biologic studies.”

The researchers reported their findings in the December 2013 issue of Genes, Chromosomes and Cancer.

Acquired Mutations in Metastatic Cells

In addition to the CNA profiles that were shared by some primary tumors and their metastasis counterparts, the researchers also found CNAs that were present only in metastatic tumors, suggesting these variations were acquired some time after the cancer had spread. These acquired mutations may provide clues to how cancer cells are able to enter the brain and survive.

One of the acquired CNAs was located in the DNA region containing the gene TERT, which can stimulate the production of a cancer-promoting protein called telomerase. The end result of the TERT alterations could be increased telomerase activity, which allows the metastatic cancer cells to continue dividing without dying.

“Finding acquired genetic alterations associated with TERT suggests that the gene plays an important role in enabling metastatic neuroblastoma to go to the brain and survive — although this also needs to be proven in the lab,” Dr. Cheung says.

He explained that increased levels of the TERT protein and telomerase activity have been well documented as playing a key role in cancer cell survival, but the present study suggests they may occur in neuroblastoma by a previously unknown genetic mechanism.

“Our findings support targeting telomerase to treat neuroblastoma,” he says. “Drugs that inhibit telomerase are already being tested in clinical trials. Our study suggests that a strategy of telomerase inhibition could be effective against more neuroblastoma subtypes than previously anticipated.”

Read about Emily Wang, who was successfully treated for neuroblastoma brain metastases by Dr. Cheung and other Memorial Sloan Kettering specialists.