Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review

Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder that carries a higher risk of tumor development. Plexiform neurofibromas (PNs) are present in 50% of NF1 and cause significant morbidity when surgery is not feasible. Systemic therapies had not succeeded to reduce PN tumor volume until 2016 when the first trial with an MAPK/extracellular-signal-regulated kinase (MEK) inhibitor was published. We performed a systematic research on novel targeted therapies for patients with NF1 and PNs in PubMed, EMBASE, and conference abstracts with the last update in February 2021. Since 2016, seven trials have reported positive results with MEK inhibitors and other molecular targeted therapies (cabozantinib). Selumetinib has shown an overall response rate of 68% in children with NF1 and symptomatic inoperable PNs, and was associated with pain improvement and a manageable adverse events profile. This led to Food and Drug Administration (FDA) approval of selumetinib in May 2020. Recently, cabozantinib and mirdametinib have also proven their efficacy in adult population. Other MEK inhibitors such as trametinib and binimetinib have also communicated promising preliminary results. Ongoing trials in different populations and with intermittent dosing strategies are underway.

Ca2+ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling

“…Mirdametinib and selumetinib, two selective MEK non-ATPcompetitive inhibitors [59], have been proved to be effective to treat the Neurofibromatosis type 1 patients [60,73]. Selumetinib was approved by Food and Drug Administration (FDA) in May 2020 [60].…”

“…Mirdametinib (PD0325901) is a potent inhibitor of MEK/ERK pathway [45,59] and has been proved to be effective in treating adult neurofibromatosis type 1 patients [60]. To test our hypothesis, we treated pregnant females daily through intraperitoneal injection with mirdametinib between E14.5 and E16.5 spanning the developmental period for CC formation, and harvested the embryos at E17.5 (Fig.…”

Novel Biomarkers and Therapeutic Targets for Melanoma

“…For patients with non-resectable, metastatic, BRAF-mutant melanomas, BRAF/MEK inhibitor treatment can prolong progression-free survival and overall survival [ 20 ]. The combination of BRAF and MEK inhibitors is also effective as an adjuvant therapy for stage III melanoma patients in terms of disease-free survival [ 30 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ].…”

“…The greatest evidence of this achieved so far is related to treatment with MEK inhibitors for NF1-mutant melanoma [ 59 , 60 ]. Although therapeutic response to MEK inhibitors is impressive, a long period of treatment is necessary to achieve this response [ 61 ]. Immunotherapy and targeted therapy are both found to be effective for the treatment of NF1-mutant melanoma; however, further studies are required to determine the best treatment protocol with minimal side effects.…”

Recommendations of the Polish Sarcoma Group on diagnostic-therapeutic procedures and control in patients with type 1 neurofibromatosis (NF1) and the associated malignant neoplasm of peripheral nerve sheaths

“…In 2020 in the United States a MEK inhibitor -selumetinib was registered for treating pediatric patients with symptomatic and/or progressing nonresectable PN associated with NF1. In clinical trial NCT01362803, which analyzed the effect of selumetinib on noresectable plexiform neurofibromas in the course of type 1 neurofibromatosis, children aged from 3 to 18 years took part [54][55][56]. Registration was performed on the basis of the above one-armed trial in 50 patients with NF1 with symptomatic, nonresectable PN.…”