Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1

Semenova, Galina; Stepanova, Dina; Deyev, Sergey M.; Chernoff, Jonathan

doi:10.1016/j.biochi.2017.01.001

Cited by 9 publications

(10 citation statements)

References 20 publications

(26 reference statements)

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“…The experimental validation of the therapeutic effectiveness of drugs retrieved by NFFinder to treat NF1-associated MPNST was reported for HDAC inhibitors [ 28 ], cantharidin [ 29 ] and tamoxifen [ 30 ], and clinical trials have been suggested for all of them. The conclusion of our in-silico workflow ( Fig 2 ) with these experimental data confirms the predictive value of the MPNST vs. NF gene signature and its usefulness to identify robust biomarkers and therapeutic agents in neurofibromatosis disease.…”

Section: Resultsmentioning

confidence: 99%

“…The protein phosphatase 2A inhibitor cantharidin was found by screening from a library of 472 small bioactive compound library [29] and shown to avoid growth of NF1-associated MPNST cultured cells, though additional studies should clarify the relevance of cantharidin in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…Cantharidin and tamoxifen were also retrieved by NFFinder and confirmed experimentally as effective drugs to inhibit MPNST cultured cell proliferation and survival. The protein phosphatase 2A inhibitor cantharidin was found by screening from a library of 472 small bioactive compound library [ 29 ] and shown to avoid growth of NF1-associated MPNST cultured cells, though additional studies should clarify the relevance of cantharidin in vivo .…”

Section: Discussionmentioning

confidence: 99%

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Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

et al. 2017

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Benign neurofibromas, the main phenotypic manifestations of the rare neurological disorder neurofibromatosis type 1, degenerate to malignant tumors associated to poor prognosis in about 10% of patients. Despite efforts in the field of (epi)genomics, the lack of prognostic biomarkers with which to predict disease evolution frustrates the adoption of appropriate early therapeutic measures. To identify potential biomarkers of malignant neurofibroma transformation, we integrated four human experimental studies and one for mouse, using a gene score-based meta-analysis method, from which we obtained a score-ranked signature of 579 genes. Genes with the highest absolute scores were classified as promising disease biomarkers. By grouping genes with similar neurofibromatosis-related profiles, we derived panels of potential biomarkers. The addition of promoter methylation data to gene profiles indicated a panel of genes probably silenced by hypermethylation. To identify possible therapeutic treatments, we used the gene signature to query drug expression databases. Trichostatin A and other histone deacetylase inhibitors, as well as cantharidin and tamoxifen, were retrieved as putative therapeutic means to reverse the aberrant regulation that drives to malignant cell proliferation and metastasis. This in silico prediction corroborated reported experimental results that suggested the inclusion of these compounds in clinical trials. This experimental validation supported the suitability of the meta-analysis method used to integrate several sources of public genomic information, and the reliability of the gene signature associated to the malignant evolution of neurofibromas to generate working hypotheses for prognostic and drug-responsive biomarkers or therapeutic measures, thus showing the potential of this in silico approach for biomarker discovery.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

et al. 2017

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“…Novel drug targets for MPNST have also been suggested by others based on preclinical findings (Semenova et al ., ; Teicher et al ., ; Yamashita et al ., ). A recent drug screen of 63 sarcoma cell lines, including the two MPNST cell lines MPNST and ST8814, confirmed the heterogeneous responses among different soft tissue cancers (Teicher et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors

et al. 2017

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Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo‐like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity, and apoptosis. DNA copy number, gene expression, and protein expression were determined for the cell lines to assess pharmacogenomic relationships. MPNST cells were more sensitive to BI2536 and gemcitabine compared to a reference set of 94 cancer cell lines. PLK1,RRM1, and RRM2 mRNA levels were increased in MPNST compared to benign neurofibroma tissue, and the protein level of PLK1 was increased in the MPNST cell lines compared to normal Schwann cells, indicating an increased dependence on these drug targets in malignant cells. Furthermore, we observed an association between increased mRNA expression of PLK1,RRM1, and RRM2 in patient samples and worse disease outcome, suggesting a selective benefit from inhibition of these genes in the most aggressive tumors.

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“…Recent clinical trials have evaluated mitogen-activated protein kinase inhibitors for symptomatic plexiform neurofibroma[ 7 ]. Additionally, based on cell screening with a library of known bioactive compounds, we found that protein phosphatase 2, a plaque inhibitor and the calcium channel blocker nifedipine are potential therapeutic agents for NF1[ 18 ]. Identification of additional NF1 targeting molecules and good preclinical mouse models can provide a better understanding of the clinical features of NF1 and its treatment[ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Familial left cervical neurofibromatosis 1 with scoliosis: A case report

Mu¹,

Zhang²,

Shen³

et al. 2021

WJCC

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BACKGROUND Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder affecting many parts of the body with café au lait spots, skeletal deformity, and scoliosis. A familial case of NF1 with scoliosis and a painless mass had not yet been reported. CASE SUMMARY We describe the case of a 15-year-old male patient with a painless lump on the left side of his neck for 10 years and scoliosis. His right shoulder was about 5 cm lower than the left, the left side of his face was deformed, and the left submandibular skin was relaxed. The folding and drooping were obvious and movement was poor. Computed tomography revealed the involvement of the neck, upper chest wall, and surrounding left shoulder, accompanied by bone changes and scoliosis. Histological evaluation showed subepidermal pale blue mucoid degeneration, fibrous fusiform cells in the dermis in a fascicular, woven arrangement. His mother had the same medical history. The diagnosis was neurofibromatosis of the left neck. Various parts of the tumor tissue were serially resected during several visits. Eight months after surgery, there was a slight tendency to regrow. CONCLUSION This case of slow-progressing NF1 highlights the importance of early diagnosis and treatment to reduce its impact on the patient’s growth and development.

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Medium throughput biochemical compound screening identifies novel agents for pharmacotherapy of neurofibromatosis type 1

Cited by 9 publications

References 20 publications

Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

Gene signature associated with benign neurofibroma transformation to malignant peripheral nerve sheath tumors

Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors

Familial left cervical neurofibromatosis 1 with scoliosis: A case report

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