Insights from Murine Models of Neurofibromatosis Type I: The Etiology and Appropriate Therapeutic Windows for Peripheral Nerve Sheath Tumors.

Abstract

Neurofibromatosis Type I (NF1) is a common autosomal dominant disorder that afflicts approximately one in 3,500 live births. Individuals afflicted with NF1 are susceptible to developing peripheral nerve sheath tumors (PNSTs) that significantly contribute to patient morbidity and mortality. Surgical resection is the only viable option to treating these tumors. Unfortunately, in many cases, tumors arise in sensitive locations, preventing surgical resection. Thus, there is a necessity in the field of NF1 to develop effective therapies that can be used to combat these insidious tumors. In this body of work, I utilized genetically engineered mouse (GEM) models of NF1 to better characterize the natural history of PNST development. Comparative studies between different GEM models revealed a developmental sensitivity to the loss of Nf1 in plexiform neurofibroma formation. Investigations of pre-neoplastic nerves from GEM models implicate abnormally differentiated non-myelinating Schwann cells as the cell-of-origin for plexiform neurofibromas. These investigations highlighted a therapeutic window that might be leveraged to preclude late PNST development. A three step model (initiation, progression and malignant transformation) for PNST development is offered as a basis for further investigation. Improved GEM models of MPNSTs using p53 and Ink4a/Arf are utilized to investigate the role of Nf1 heterozygousity in malignant transformation. They offer several advantages over prior GEM models of MPNSTs. The Nf1 heterozygous microenvironment was found to only contribute to the progression stages of PNST development, highlighting the appropriate therapeutic window for stromal-based therapies. Rapamycin, an inhibitor of mTORC1, was investigated as a pharmacological agent to alleviate phenotypes associated with neurofibroma initiation. Preliminary trials demonstrated that rapamycin treatment can stabilize Schwann-cell/axon interactions in Nf1-deficient non-myelinating Schwann cells. Thus, rapamycin is a promising agent that fits the criteria for a drug that may preclude PNSTs from NF1 patients completely. This body of work exemplifies the utility of GEM models in identifying the etiology and appropriate therapeutic windows for inherited cancer syndromes.