8.2.5. Summary of Goals and Objectives Yuan Zhu, Ph.D. We seek to translate our preclinical findings into novel therapies for neurofibromatosis type 1 (NF1)-associated/mutated cancers in the nervous system. We will investigate three NF1-associated/mutated tumor/cancers, each of which represents a unique type of human cancer: (1) optic pathway glioma (NF1-OPG) - a benign tumor that affects visual function but has no potential for malignant transformation, (2) malignant peripheral nerve sheath tumor (NF1-MPNST) - a cancer with defined benign and premalignant lesions (plexiform and atypical neurofibroma, PNF and ANF, respectively), and (3) adult high-grade glioma and glioblastoma (GBM), a ...

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We seek to translate our preclinical findings into novel therapies for neurofibromatosis type 1 (NF1)-associated/mutated cancers in the nervous system. We will investigate three NF1-associated/mutated tumor/cancers, each of which represents a unique type of human cancer: (1) optic pathway glioma (NF1-OPG) - a benign tumor that affects visual function but has no potential for malignant transformation, (2) malignant peripheral nerve sheath tumor (NF1-MPNST) - a cancer with defined benign and premalignant lesions (plexiform and atypical neurofibroma, PNF and ANF, respectively), and (3) adult high-grade glioma and glioblastoma (GBM), a cancer with no benign precursor lesions. A recent breakthrough in the NF1 field is FDA's approval of Selumetinib, a MEK inhibitor (MEKi) for treating benign PNFs in NF1 patients. However, approval of MEKi for treating NF1-OPG requires evidence for visual improvement after MEKi treatment in children with NF1-OPG. First, we will use new genetically engineered mouse (GEM) NF1-OPG models to perform preclinical MEKi trials using non-invasive imaging and visual/functional assays to define developmental and treatment windows to preserve and improve visual function. Second, because MEKi treatment is not effective when NF1-PNFs undergo malignant transformation and progress into premalignant ANFs and MPNSTs, we will perform parallel preclinical-clinical trials using a combination of MEKi and MDM2 inhibitor to develop preventive and treatment therapies for incurable NF1-MPNSTs. Third, we will employ the new GEM models to target distant spread of p53/Nf1-mutant driven GBMs in vivo, which will provide new insights on treating GBMs in NF1 and Li-Fraumeni syndrome patients. Thus, the high cancer incidence in these syndromic patients provides an important entry point to investigate and develop preventive therapies for more common sporadic cancers with alterations in NF1/RAS and p53 pathways.

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