Prevention and Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors

Neurofibromatosis type 1 (NF1) is a common disease affecting approximately 1 in 3,000 humans. NF1 patients have an increased risk of developing a variety of neoplasms ranging from relatively benign dermal neurofibromas to highly aggressive malignant peripheral nerve sheath tumors (MPSNTs). MPNSTs are the most common malignancy associated with NF1 and occur in 10%-30% of NF1 patients. MPNSTs typically arise in NF1 patients during their 30s and 40s and lead to death on average within 5 to 8 years. Treatment of MPNSTs is unfortunately not very effective, and new strategies to prevent MPNSTs from occurring are desperately needed. It is particularly noteworthy that MPNSTs are known to frequently arise from plexiform neurofibromas, which can be identified and followed radiographically. Despite this known risk of MPNST formation from clinically detectable plexiform neurofibromas, there are no current therapies that can inhibit MPNST formation in NF1 patients.

In this application, we propose to test two different types of drugs that we hypothesize will inhibit MPNST formation in NF1 patients. The two classes of drugs are termed 'BH3 mimetics' and 'lysosomotropic agents' and both increase the susceptibility of tumor cells, including MPNST cells, to death. However, these agents have never been tested for their ability to inhibit MPNST formation in either animal models or NF1 patients. We have developed a robust transgenic mouse model that recapitulates the entire spectrum of NF1-assocatied neuropathology from Schwann cell hyperplasia -to- neurofibromas -to- MPNSTs. We propose to test BH3 mimetics and lysosomotropic agents in this model to determine if they can safely and effectively reduce MPNST formation and progression. Very importantly, the drugs to be tested in our model have already been approved for human use. For example, the lysosomotropic agent hydroxychloroquine is already chronically administered safely to patients with systemic lupus erythematosus to prevent lupus-related organ damage and increase long-term patient survival. Similarly, BH3 mimetics such as AT-101 have safely undergone numerous human clinical trials as anti-tumor agents and have been shown in several animal models to inhibit tumor formation when chronically administered.

If positive results are obtained in our preclinical mouse model, we would anticipate the rapid advancement of these agents into human use. As mentioned previously, NF1 patients with symptomatic plexiform neurofibromas have a 30% lifetime risk of developing an MPNST. Our newly developed MPNST prevention therapy could potentially dramatically decrease the risk of MPNST formation for these patients who would otherwise simply have to wait for their tumors to progress. Given that the drugs that we are testing are already approved for human use, our proposed 3-year preclinical investigation could be advanced into NF1 patients immediately upon obtaining positive results in our model.

In total, our proposal represents a potential breakthrough in NF1 patient management and could lead to a significant decrease in MPNST-associated morbidity and mortality, thus improving the lives of NF1 patients and their families.