Clinical trials targeting neurofibromatoses-associated tumors: a systematic review

Abstract

Background: There is a paucity of literature that comprehensively analyzes previous and current clinical trials targeting neurofibromatoses-related tumors. This article aims to provide readers with drug development efforts targeting these tumors by analyzing translational and clinical findings.

Methods: This systematic review was written according to the PRISMA guidelines. Inclusion criteria were clinical trials involving patients with neurofibromatosis type 1, type 2, or schwannomatosis that were treated with therapies targeting neurofibromatoses-associated tumors and that were registered on clinicaltrials.gov. In addition, a search was performed in PubMed, Web of Science, Google Scholar, and Embase European for articles fully describing these clinical trials.

Results: A total of 265 clinical trials were registered and screened for eligibility. Ninety-two were included in this systematic review involving approximately 4636 participants. The number of therapies analyzed was more than 50. Drugs under investigation mainly act on the MAPK/ERK and PI3K/AKT/mTOR pathways, tumor microenvironment, or aberrantly over-expressed cell surface receptors. Selumetinib was the most effective medication for treating a neurofibromatosis type 1-associated tumor with approximately 68%-71% partial response for inoperable or progressive plexiform neurofibromas in children 2 years of age and older and bevacizumab for a neurofibromatosis type 2-related tumor with approximately 36%-41% partial response for vestibular schwannomas in patients 12 years of age and older.

Conclusions: This systematic review presents the results of previous clinical investigations and those under development for neurofibromatoses-associated tumors. Clinicians may use this information to strategize patients to appropriate clinical trials.

Keywords: clinical trials; neurofibromatosis type 1; neurofibromatosis type 2; schwannomatosis; therapies.

Figure 1.

Main regulatory pathways involved in NF1 and NF2 mutations associated tumorigenesis with therapies under evaluation. Mutations in the NF suppressor genes cause loss of negative regulation in multiple pathways, leading to cancer cell proliferation, growth, and survival. Current drugs are not specific in targeting pathologic mechanisms. MEK and BRAF inhibitors act on the MAPK pathway, mTOR inhibitors on the PI3K/AKT/mTOR pathway, and farnesyl transferase inhibitors disrupt RAS signaling. Inflammation contributes to tumor development and progression and is potentiated with the recruitment of various cells, including endothelial cells, mast cells, macrophages, and fibroblasts. VEGFR, VEFG-A, KIT, and CSF1R inhibitors block the microenvironment inflammatory cells activity. There is also the possibility of evoking an immune response with interferon and potentially utilizing immune checkpoint therapies (pembrolizumab, nivolumab). Other anti-tumorigenesis mechanisms include inhibiting aberrantly over-expressed cell surface receptors (MET, KIT, PDGFR, EGFR), slowing metabolism with glutaminase inhibitors, and accumulation of unfolded proteins in the endoplasmic reticulum lumen with heat shock protein 90 inhibitors. A novel approach uses the injectable measles virus Edmonston vaccine strain engineered to express the human sodium–iodide symporter and induce cell death..

Figure 2.

Four hit/3-step model of tumorigenesis in schwannomatosis. The mutated germline SMARCB1 or LZTR1 gene copy is kept in the tumor (hit 1), the totality or part of chromosome 22 containing the wildtype SMARCB1 or LZTR1 gene copy and a wildtype copy of the NF2 gene is lost (hits 2 and 3), followed by a somatic mutation in the remaining wildtype NF2 gene copy (hit 4)..

Figure 3.

PRISMA flow diagram.