Preclinical Therapeutic Efficacy of a Novel Pharmacologic Inducer of Apoptosis in Malignant Peripheral Nerve Sheath Tumors

Chau, Vincent; Lim, Sang Kyun; Mo, Wei; Liu, Chiachi; Patel, Aditi; McKay, Renée M.; Wei, Shuguang; Posner, Bruce A.; Brabander, Jef K. De; Williams, Noelle S.; Parada, Luis F.; Le, Lu Q.

doi:10.1158/0008-5472.can-13-1934

Cited by 26 publications

(33 citation statements)

References 47 publications

(57 reference statements)

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“…Bioluminescent imaging was performed as described previously (Chau et al, 2014). Briefly, mice were injected with 160 uL 20 mg/mL D-Luciferin Potassium Salt (Perkin Elmer) in 0.9% sterile NaCl, and total flux was quantified using IVIS Lumina II (Caliper Life Sciences) weekly.…”

Section: Methodsmentioning

confidence: 99%

Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

et al. 2014

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Summary Neurofibromatosis type 1 is a tumor-predisposing genetic disorder. Plexiform neurofibromas are common NF1 tumors carrying a risk of malignant transformation, which is typically fatal. Little is known about mechanisms mediating initiation and identity of specific cell-type that gives rise to neurofibromas. Using cell-lineage tracing, we identify a population of GAP43+ PLP+ precursors in embryonic nerve roots as the cells of origin for these tumors and report a non-germline model of neurofibroma for preclinical drug screening to identify effective therapies. The identity of tumor cell-of-origin and facility for isolation and expansion provides fertile ground for continued analysis to define intrinsic and extrinsic factors critical for neurofibromagenesis. It also provides unique approaches to develop therapies to prevent neurofibroma formation in NF1 patients.

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Section: Methodsmentioning

confidence: 99%

Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

et al. 2014

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“…Screening a library of 200,000 small molecules on mouse Nf1 -mutant MPNST cells identified compound 21, with selectivity towards NF1 -mutant cells and efficacy in xenografts 173 . Another library-screening study identified UC1 as a small molecule that targets NF1 −/− versus sporadic MPNST cell lines.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

2015

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Neurofibromatosis type 1 (NF1) is a common genetic disorder that predisposes affected individuals to tumours. The NF1 gene encodes a RAS GTPase-activating protein called neurofibromin and is one of several genes that (when mutant) affect RAS–MAPK signalling, causing related diseases collectively known as RASopathies. Several RASopathies, beyond NF1, are cancer predisposition syndromes. Somatic NF1 mutations also occur in 5–10% of human sporadic cancers and may contribute to resistance to therapy. To highlight areas for investigation in RASopathies and sporadic tumours with NF1 mutations, we summarize current knowledge of NF1 disease, the NF1 gene and neurofibromin, neurofibromin signalling pathways and recent developments in NF1 therapeutics.

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“…PRC2 loss led to increased levels of acetylated histone H3 of lysine 27 (H3K27Ac), which recruits bromodomain proteins [14]. MPNST cell lines were shown to be sensitive to bromodomain inhibitors [12, 15]. …”

Section: Introductionmentioning

confidence: 99%

Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells

et al. 2016

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Approximately 30-50% of individuals with Neurofibromatosis type 1 develop benign peripheral nerve sheath tumors, called plexiform neurofibromas (PNFs). PNFs can undergo malignant transformation to highly metastatic malignant peripheral nerve sheath tumors (MPNSTs) in 5-10% of NF1 patients, with poor prognosis. No effective systemic therapy is currently available for unresectable tumors. In tumors, the NF1 gene deficiency leads to Ras hyperactivation causing the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways and inducing multiple cellular responses including cell proliferation. In this study, three NF1-null MPNST-derived cell lines (90-8, 88-14 and 96-2), STS26T sporadic MPNST cell line and PNF-derived primary Schwann cells were used to test responses to AZD8055, an ATP-competitive “active-site” mTOR inhibitor. In contrast to rapamycin treatment which only partially affected mTORC1 signaling, AZD8055 induced a strong inhibition of mTORC1 and mTORC2 signaling in MPNST-derived cell lines and PNF-derived Schwann cells. AZD8055 induced full blockade of mTORC1 leading to an efficient decrease of global protein synthesis. A higher cytotoxic effect was observed with AZD8055 compared to rapamycin in the NF1-null MPNST-derived cell lines with IC50 ranging from 70 to 140 nM and antiproliferative effect was confirmed in PNF-derived Schwann cells. Cell migration was impaired by AZD8055 treatment and cell cycle analysis showed a G0/G1 arrest. Combined effects of AZD8055 and PD0325901 MEK inhibitor as well as BRD4 (BromoDomain-containing protein 4) inhibitors showed a synergistic antiproliferative effect. These data suggest that NF1-associated peripheral nerve sheath tumors are an ideal target for AZD8055 as a single molecule or in combined therapies.

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Preclinical Therapeutic Efficacy of a Novel Pharmacologic Inducer of Apoptosis in Malignant Peripheral Nerve Sheath Tumors

Cited by 26 publications

References 47 publications

Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

Cells of Origin in the Embryonic Nerve Roots for NF1-Associated Plexiform Neurofibroma

A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor

Dual mTORC1/2 inhibition induces anti-proliferative effect in NF1-associated plexiform neurofibroma and malignant peripheral nerve sheath tumor cells

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