The optic pathway glioma (OPG), a brain tumor composed of neoplastic Nf1-deficient astrocytes, is the second most common tumor in individuals affected with neurofibromatosis 1 (NF1). We have recently developed and extensively characterized a mouse model of NF1-associated OPG in which low-grade tumors develop by 2 months of age. In addition, we have employed this unique mouse model to identify new molecular targets for NF1 brain tumor therapy. To provide an efficient approach for the identification, initial validation, and in vivo preclinical evaluation of new anticancer compounds suitable for patients with NF1-associated brain tumors, we have initiated a multidisciplinary therapeutic discovery program. Using this approach, we have identified two potential targets for NF1 brain tumor therapy, rapamycin and AMD3100. Both of these compounds result in inhibition of Nf1-/- astrocyte growth in vitro.

The primary objective of the proposed research is twofold: (1) to validate the Nf1 OPG mouse model as a preclinical drug testing platform and (2) identify new anticancer compounds suitable for the treatment of NF1-associated brain tumors. We will analyze two lead compounds (rapamycin and AMD3100) for their ability to inhibit OPG formation and growth in Nf1 OPG mice in vivo. Tumor growth will be monitored by small animal magnetic resonance imaging (MRI). In addition, we plan to employ high-throughput chemical library screening to identify new compounds that inhibit the growth of Nf1-deficient astrocytes. Candidate compounds will next be validated in vitro using Nf1-deficient astrocytes, and their mechanism(s) of action will be determined to lay the groundwork for future evaluation in vivo.

While NF1-associated OPG are often regarded as "benign" brain tumors, their continued growth can result in loss of vision and hypothalamus dysfunction (early puberty). Currently, therapy for NF1 OPG is based on the use of compounds that have been successfully employed to treat other low-grade brain tumors. As we enter the age of tailored anticancer therapy, it is important to develop high-throughput approaches to the identification, initial validation, and preclinical evaluation of potential therapeutic agents. With the generation and characterization of Nf1 OPG mice in our laboratory, we are uniquely positioned to establish such a program.