Pharmacological Approaches in Neurofibromatosis Type 1-Associated Nervous System Tumors

Abstract

Neurofibromatosis type 1 is an autosomal dominant genetic disease and a common tumor predisposition syndrome that affects 1 in 3000 to 4000 patients in the USA. Although studies have been conducted to better understand and manage this disease, the underlying pathogenesis of neurofibromatosis type 1 has not been completely elucidated, and this disease is still associated with significant morbidity and mortality. Treatment options are limited to surgery with chemotherapy for tumors in cases of malignant transformation. In this review, we summarize the advances in the development of targeted pharmacological interventions for neurofibromatosis type 1 and related conditions.

Keywords: NF1 models; gene therapy; glioma; malignant peripheral nerve sheath tumor; neurofibroma; neurofibromatosis type 1; noncoding RNA; targeted therapy; tumor microenvironment.

Figure 1

Targetable pathways in NF1. A plethora of signaling pathways has been implicated in MPNST growth and progression. These pathways include growth signaling pathways, tumor suppressors, pathways that are involved in metabolism and development, and pathways that are involved in angiogenesis and immune responses. Pathways and their targeted drugs are represented schematically in this figure. Loss of NF1 protein leads to the activation of RAS/RAF/MEK and TSC2/mTOR signaling pathways, which support cancer cell proliferation. Dysregulation of cell cycle checkpoints, such as CDK2NA and p27, led to abnormal levels of cell cycle kinase CDK4/6 and CDK2, which support cancer cell growth and proliferation. Growth receptor aberrations also contribute to MPNST pathogenesis. Examples of the aberrant receptor signaling that can be targeted are EGFR, c-Met, and PDGFR. Some signaling pathways that are involved in cell development and stemness have been implicated in MPNST development. These are represented by the Wnt and Hippo pathways. Targeting tumor microenvironments is another strategy to treat MPNSTs. Drugs that target the tumor microenvironment include bevacizumab, which targets pro-angiogenic VEGF pathways, and imatinib and pexidatrininb which target mast cells and macrophages, respectively, and play pro-tumorigenic role. Immune checkpoint inhibitors are other examples of drugs in this category. Other targets that are represented are involved in metabolism (glutaminase), epigenetic (BRD4), and ER stress (Hsp90).