John M. Maris, MD

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June 18, 2012

Editorial Collaboration

Medscape &

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My name is John Maris. I am the chief of the Division of Oncology at The Children's Hospital of Philadelphia (CHOP). Today, I'd like to talk to you about a very exciting research study that was presented at the most recent American Society of Clinical Oncology (ASCO®) meeting in Chicago by Dr. Yael Mossé, on behalf of her colleagues at CHOP and the Children's Oncology Group.

This major cancer meeting highlights the most exciting research across the country -- across the world, even. Dr. Mossé presented the results of a study of a drug called crizotinib for treating pediatric cancers, particularly pediatric neuroblastoma and pediatric lymphoma.

The study highlights the move toward a much more personalized approach to treating cancer. It is not one-size-fits-all. There is not a drug that is going to treat all neuroblastomas or all lymphomas. We are going to get at specific abnormalities that may be present in different types of cancers. Those different cancers are vulnerable to a specific drug if it is targeted in a specific way.

This all started many years ago, with Dr. Mossé's discovery of mutations in the anaplastic lymphoma kinase (ALK) gene. These mutations were the cause of a hereditary neuroblastoma that sometimes made neuroblastomas much more aggressive. These mutations could turn the cancer cells on and make them grow and divide more rapidly.

What that discovery opened up was the possibility of studying whether or not a drug that inhibited ALK would impact neuroblastoma. It also gave Dr. Mossé and her colleagues the opportunity to see whether this type of drug worked in other cancers. When we find these sorts of targets, we often like to ask the question, "Yes, it might work in one particular disease, but does it work in other diseases?"

This gene is called anaplastic lymphoma kinase because it was originally discovered to be abnormal in a rare type of lymphoma called anaplastic large cell lymphoma. While that has been known for many years, there really has not been a targeted approach to take advantage of this knowledge. ALK is mutated in lymphoma in a different way: The gene is broken apart and brought back together in a translocation rather than a mutation. The commonality is that both in neuroblastoma and lymphoma, these mutations in ALK are driving the cancer.

The results of the study show that there were dramatic responses in all of the cases of lymphoma where there was this abnormality in the translocation and in many of the children who had neuroblastoma. This was a dose-finding study, meaning that the dose levels were started low and then raised through the study. Often in these dose-finding studies, there are no responses, or maybe a hint of a response. However, the results that Dr. Mossé has presented are very encouraging. Typically, these studies help us decide whether we want to continue to study a drug. This study delivers on that goal, and more so. There is a tremendous amount of enthusiasm.

What this also shows is that we need to get to a point in pediatric cancer practice, and in all cancer practice, where we can access the tumor tissue to ask the question of whether or not ALK is mutant. In this study, because it was not a requirement to know that, there were many children who did not respond, as well as some children who did respond in whom we do not know whether the ALK gene was mutated or translocated.

This is a very important lesson from this study: When you know this information, you can leverage it and use it therapeutically. However, getting this information is often very difficult. In children, lymphomas or neuroblastomas in the relapse setting can often be difficult to get at for a surgeon.

We are in a new era where we have to think of creative ways to access these cancer cells to ask these important questions. Because now, this is a perfect example where we can take that information and, hopefully, positively impact the patient and make their cancer go away.

In summary, crizotinib is an exciting new drug for pediatric neuroblastomas and pediatric lymphomas. There is also evidence from Dr. Mossé's study that it works in a rare type of sarcoma called inflammatory myofibroblastic tumor. The commonality is not the disease type, but the mutation in ALK and the fact that ALK is driving these. Research now is going to be looking at which pediatric and adult cancers are addicted to or driven by ALK. There is a subset of lung cancers that are driven by ALK. This study helps us get to the place where we are asking not what the disease is, in a broad sense, but what is the mutation or abnormality and taking advantage of that information.

Thank you for your attention.

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