Emerging therapeutic targets for neurofibromatosis type 1

Walker, James A.; Upadhyaya, Meena

doi:10.1080/14728222.2018.1465931

Cited by 68 publications

(58 citation statements)

References 151 publications

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“…The two young children with developmental delay have demonstrated developmental catch up, which is likely multifactorial. It remains to be elucidated whether early MEK inhibition will have a positive effect on neurodevelopment in patients with NF‐1 37 . Unfortunately, long‐term effects of this medication are not known when used in such young patients.…”

Section: Discussionmentioning

confidence: 99%

Trametinib therapy for children with neurofibromatosis type 1 and life‐threatening plexiform neurofibroma or treatment‐refractory low‐grade glioma

et al. 2021

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Purpose To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib. Methods We report on six patients with NF‐1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively. Results Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4–28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life‐threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1–2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy. Conclusion Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF‐1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

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Section: Discussionmentioning

confidence: 99%

Trametinib therapy for children with neurofibromatosis type 1 and life‐threatening plexiform neurofibroma or treatment‐refractory low‐grade glioma

et al. 2021

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“…Topiramate is an FDA-approved GRIK5 inhibitor employed as an anti-epileptic drug and is used to manage seizures and prevent migraines (75). Neurofibromin 1(NF1) is ubiquitously expressed; however, its highest levels are found in cells of the central nervous system and it has been described to function as a negative regulator of the Ras signal transduction pathway (76, 77). Trametinib is an NF1 inhibitor which is also known as a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor with anticancer activity and is FDA-approved for use in metastatic malignant melanoma (78).…”

Section: Resultsmentioning

confidence: 99%

A two-color haploid genetic screen identifies novel host factors involved in HIV latency

Röling

Sisakht

et al. 2021

Preprint

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To identify novel host factors as putative targets to reverse HIV latency, we performed an insertional mutagenesis genetic screen in a latently HIV-1-infected pseudo-haploid KBM7 cell line (Hap-Lat). Following mutagenesis, insertions were mapped to the genome and bioinformatic analysis resulted in the identification of 69 candidate host genes involved in maintaining HIV-1 latency. A select set of candidate genes was functionally validated using shRNA mediated depletion in latent HIV-1 infected J-Lat A2 and 11.1 T cell lines. We confirmed ADK, CHD9, CMSS1, EVI2B, EXOSC8, FAM19A, GRIK5, IRF2BP2, NF1, and USP15 as novel host factors involved in the maintenance of HIV latency. Chromatin immunoprecipitation assays indicated that CHD9, a Chromodomain Helicase DNA-binding protein, maintains HIV latency via direct association with the HIV 5’LTR, and its depletion results in increased histone acetylation at the HIV-1 promoter, concomitant with HIV-1 latency reversal. FDA-approved inhibitors 5-Iodotubercidin, Trametinib, and Topiramate, targeting ADK, NF1, and GRIK5, respectively were characterized for their latency reversal potential. While 5-Iodotubercidin exhibited significant cytotoxicity in both J-Lat and primary CD4+ T cells, Trametinib reversed latency in J-Lat cells but not in latently HIV-1-infected primary CD4+ T cells. Crucially, Topiramate reversed latency in cell-line models and latently infected primary CD4+ T cells, without inducing T cell activation or significant toxicity. Thus, using an adaptation of a haploid forward genetic screen, we identified novel and druggable host factors contributing to HIV-1 latency.ImportanceA reservoir of latent HIV-1-infected cells persists in the presence of combination antiretroviral therapy (cART), representing a major obstacle for viral eradication. Reactivation of the latent HIV-1 provirus is part of curative strategies which aim to promote clearance of the infected cells. Using a two-color haploid screen, we identified 69 candidate genes as latency maintaining host factors and functionally validated a subset of 10 of those in additional T-cell based cell line models of HIV-1 latency. We further demonstrated that CHD9 is associated with HIV-1’s promoter, the 5’LTR while this association is lost upon reactivation. Additionally, we characterized the latency reversal potential of FDA compounds targeting ADK, NF1, and GRIK5 and identify the GRIK5 inhibitor Topiramate as a viable latency reversal agent with clinical potential.

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“…One of the major hopes for future therapies is using possible gene strategies to restore the malfunction of the NF1 gene by non-sense suppression and exon skipping to correct neurofibromin deficiency ( 121 , 122 ). Personalized therapeutic approaches integrating genome editing technology could be used as promising and radical treatments once we fully understand the genotype–phenotype correlations and the important role of modifiers of NF1 ( 123 ). However, current studies are not enough to fully understand the genotype–phenotype correlations and heterogeneity of genes in NF1 patients.…”

Section: Discussionmentioning

confidence: 99%

Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1

et al. 2021

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Neurofibromatosis type 1 (NF1) is a tumor predisposition genetic disorder that directly affects more than 1 in 3,000 individuals worldwide. It results from mutations of the NF1 gene and shows almost complete penetrance. NF1 patients show high phenotypic variabilities, including cafe-au-lait macules, freckling, or other neoplastic or non-neoplastic features. Understanding the underlying mechanisms of the diversities of clinical symptoms might contribute to the development of personalized healthcare for NF1 patients. Currently, studies have shown that the different types of mutations in the NF1 gene might correlate with this phenomenon. In addition, genetic modifiers are responsible for the different clinical features. In this review, we summarize different genetic mutations of the NF1 gene and related genetic modifiers. More importantly, we focus on the genotype–phenotype correlation. This review suggests a novel aspect to explain the underlying mechanisms of phenotypic heterogeneity of NF1 and provides suggestions for possible novel therapeutic targets to prevent or delay the onset and development of different manifestations of NF1.

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Emerging therapeutic targets for neurofibromatosis type 1

Cited by 68 publications

References 151 publications

Trametinib therapy for children with neurofibromatosis type 1 and life‐threatening plexiform neurofibroma or treatment‐refractory low‐grade glioma

Trametinib therapy for children with neurofibromatosis type 1 and life‐threatening plexiform neurofibroma or treatment‐refractory low‐grade glioma

A two-color haploid genetic screen identifies novel host factors involved in HIV latency

Impacts of NF1 Gene Mutations and Genetic Modifiers in Neurofibromatosis Type 1

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