Although the NF1 gene was identified over 15 years ago, very little is known about how the NF1 protein, neurofibromin, normally functions to control cell growth. Our group identified the first mechanism known to regulate neurofibromin a few years ago. Specifically, we showed that in response to growth signals neurofibromin is rapidly turned off. However, soon thereafter it is turned on again in order to appropriately limit this growth signal.

The goals of this proposal are to identify the proteins that turn neurofibromin on and off and to get a better understanding of how this occurs. Importantly, we have identified two proteins that turn neurofibromin off, which will be further studied in this proposal. Notably, therapeutic agents that inhibit these proteins exist and are currently in clinical trials for other tumor types. Therefore, these drugs may represent novel therapeutic agents that may be effective in treating some of the symptoms that develop in patients with NF1, by keeping neurofibromin on and active. How would these drugs work if the NF1 gene is mutated in NF1 patients? There are several disease symptoms whose mere reduction of NF1 protein levels, rather than complete loss, underlies their development. Learning disabilities, bone deformations, and vascular abnormalities are three examples of important, nontumorigenic symptoms of this type. In addition, we now know that neurofibromas, one of the most common and life-altering features of NF1, are caused by both NF1-deficient cells as well as cells with only one intact copy of the gene. Therefore, in these tumors, surrounding NF1 +/- cells (with only 1 mutation) represent a novel therapeutic target cell population. Specifically, one therapeutic strategy would be to utilize a drug that causes an increase in neurofibromin levels in these cells. As a result, the defect in "gene dosage" would be corrected and these cells would function normally. In fact, both of the agents mentioned above appear to do this.

Finally, while the first two aims of this proposal are designed to understand how the NF1 protein is regulated and normally functions to control cell growth, the third aim is focused on understanding how loss of NF1 leads to tumor development. Specifically, we have been examining this in astrocytomas. NF1 patients develop astrocytomas in the brain and in the optic pathway. Fortunately, these tumors are usually benign and typically do not progress to malignancy. However, these lesions can impair/destroy vision in NF1 patients. We have found that loss of NF1 causes astrocytoma cells to initially grow but then become dormant. In this proposal we are trying to understand how these cells become dormant and determine if we can convert the "dormancy signal" to a "cell death" signal. If we are able to do this then perhaps we will be able to design a therapy to cause regression of these astrocytomas. If our hypothesis is correct then there is already a well-tolerated drug in existence that may be useful in treating these lesions. Importantly, this therapy may also extend to neurofibromas as well. The NF1 field is now at a stage in which there are a few therapeutic agents that can be tested in clinical trials. However, different symptoms are likely to require different therapeutic agents. In addition, it is likely that some symptoms will require a combination of different drugs. Finally, it is important that the field continues to identify agents with minimal toxicity. Therefore, it is critical that, as a field, we continue to perform basic scientific studies aimed at further understanding the biological function of the NF1 protein and the role mutations play in the tumorigenic process. If this occurs we can continue to identify new therapeutic targets, begin testing them in animal models, and bring them to clinical trials as quickly as possible. The long-term success of this endeavor is likely to hinge on continuing to support this multi-faceted pipeline.