Neuropathology Division
   Brain Tumor Research

July 2008

Dear Supporters of Pilocytic and Pilomyxoid Astrocytoma Research,

We have an exciting discovery to tell you about. Over the last few months, we have completed the major goal put forward in our initial proposal – to identify a common molecular change in pilocytic tumors. Recall that unlike many other brain tumor types, until now it was not known what genes, if any, were important in the majority of pilocytic astrocytomas. We are particularly excited by our discovery as the genetic change we have found is a very good target for new therapies. Ultimately, as we discuss below, we hope this will translate into improved treatment options for curing children with these tumors.

As we mentioned in our last update sent in March 2008, our molecular analysis of 25 pilocytic astrocytomas identified a small region of Chromosome 7 that was gained in 17 (68%) of the cases we analyzed. This is by far the most common genetic change identified in pilocytic tumors to date. The altered region contains just 17 genes, and we now believe that we have identified one, known as “BRAF”, that plays a key role in pilocytic tumors. We have shown that the molecular pathway controlled by BRAF is turned on in the majority of pilocytic astrocytomas, including both the tumors used in our initial study, and additional cases which served as an independent control set. The BRAF pathway is also commonly active in melanomas and thyroid tumors. That is very important, because it has already led pharmaceutical companies to develop a number of drugs that can turn the BRAF pathway off. These drugs will potentially be able to help children with piloid tumors. Our paper describing this work has been accepted for publication in the Journal of Neuropathology and Experimental Neurology, and we will send you copies as soon as it is released. Four other groups have very recently reported identifying the same general region of change in pilocytic astrocytomas, and at least two of these also feel BRAF is activated by the change. This makes us even more confident that BRAF represents a key potential target for new therapies.

The Next Steps

Our immediate plans are to determine if the BRAF pathway is also active in pilomyxoid lesions, as well as in other types of low grade pediatric astrocytoma, including infiltrating grade II astrocytomas. We are also working to see if the drugs developed to block BRAF will stop the growth of pilocytic and pilomyxoid astrocytomas. To accomplish this, it is critical that we continue to make progress on our new models of piloid tumors. As we mentioned two years ago in our initial grant proposal, no proven mouse or cell culture models of pilocytic or pilomyxoid astrocytomas exist. Without such models, it will be very difficult to translate our new molecular discoveries into potential cures that can be tested in patients. We have been successful in keeping pilocytic astrocytomas resected at Johns Hopkins growing for up to a year in culture, and plan to use some of these cells to test prospective chemotherapeutic agents targeting BRAF. However, none of the tumor cell lines we have developed to date are as robust as we would like, and we need to continue to try to optimize conditions for the growth of such pilocytic tumor cells both in plastic culture dishes and in special mice that lack a fully functional immune system.

We are also planning a new longer-term goal based on our discovery: the development of a mouse model for these tumors. We are excited by the possibility that we can generate "transgenic" mice whose brains contain the BRAF change found in humans. Hopefully, these animals will develop pilocytic brain tumors, and can then be used to test new drugs. As we discuss below, this ongoing research will require more support.

Additional support

Your generous financial support has been instrumental in getting us to this point, and we hope you will continue to help fund our work as we move forward translating the molecular discoveries we have made into new potential cures. As we mentioned in our last update, it is not clear if the Childen’s Cancer Foundation grant we obtained for 2007-2008 will be renewed, and we will be unable to move ahead with our studies without new funding after that grant has lapsed. Your ongoing support will therefore be critical if more advances are to be achieved.

Our main goals over the next two years are to:

  1. Continue to develop pilocytic and pilomyxoid cell culture models.
  2. Test the effects of BRAF inhibitors in these cells.
  3. Develop new "transgenic" mouse models for pilocytic astrocytoma based on activation of BRAF in the brain.
  4. Determine if BRAF activation is also present in pilomyxoid tumors.
  5. Support Dr. Cohen with the pilomyxoid registry, which is now operational and will hopefully lead to new insights on the best use of existing treatments for these tumors.
  6. Complete and publish Dr. Burger’s study of the microscopic features that differentiate pilomyxoid tumors from pilocytic ones.
  7. Complete and publish our study of Notch signaling in pilocytic astrocytomas.

Thank you once again for your investment and partnership! You have truly been instrumental in initiating a large number of projects and moving them forward.

Best Regards,

Charles Eberhart, M.D., Ph.D. and Peter Burger, M.D.