Odontogenic keratocysts(OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome(NBCCS). OKCs are locally aggressive, ca...Odontogenic keratocysts(OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome(NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations(at ～80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog(SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1^(R135 X/+) cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403 C>T(p.R135 X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated 9(Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 R135 X/+heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.展开更多
The Hedgehog(Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development.Gain and loss of function of Hh signalling are known to result in an array of craniofacial m...The Hedgehog(Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development.Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 or 150 mg·kg^(-1) body weight at preselected time points between embryonic days(E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg·kg^(-1). Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death.展开更多
Objective: To review and evaluate vismodegib, the first US Food and Drug Administration (FDA) approved treatment for locally advanced (laBCC) or metastatic basal cell carcinoma (mBCC) that has recurred after surgery o...Objective: To review and evaluate vismodegib, the first US Food and Drug Administration (FDA) approved treatment for locally advanced (laBCC) or metastatic basal cell carcinoma (mBCC) that has recurred after surgery or for patients in which surgery or radiation is not an option. Data Sources: A literature search using PubMed was conducted through January 2013, using the terms vismodegib, GDC-0449, and Erivedge. Additional literature was found through the reference citations of identified articles. Study Selection and Data Extraction: Potential sources were limited to human studies published in English with a priority placed on those focused on laBCC or mBCC. Data Synthesis: Vismodegib is a selective inhibitor of the hedgehog (Hh) pathway approved for the treatment of laBCC or mBCC that has recurred after surgery, or for patients for whom surgery or radiation is contraindicated. Vismodegib inhibits cancer cell growth and survival by binding Smoothened, a transmembrane protein involved in the Hedgehog signal transduction. Vismodegib is administered orally at a dose of 150 mg daily. It is primarily eliminated through the feces unchanged but does have some oxidative metabolites produced from the recombinant cytochrome P450 (CYP) 2C9 and CYP3A4/5. Despite CYP450 involvement, it appears to have very few drug interactions. The most common adverse events reported with vismodegib include muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, anorexia, and diarrhea. FDA approval was based on a single arm phase II study that demonstrated an objective response rate of 30% in mBCC patients and 45% in laBCC patients. Vismodegib was approved by the FDA on January 30, 2012 for use in patients with advanced basal cell carcinoma, and continues to be studied in other patient populations for additional potential uses. Conclusions: Based on a review of current evidence, vismodegib provides an effective and well-tolerated treatment for otherwise untreatable basal cell carcinoma.展开更多
基金supported by the National Natural Science Foundation of China (81671006, 81300894)Beijing Natural Science Foundation (7172238)
文摘Odontogenic keratocysts(OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome(NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations(at ～80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog(SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1^(R135 X/+) cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403 C>T(p.R135 X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated 9(Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 R135 X/+heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.
基金supported by the National Natural Science Foundation of China (31070838)
文摘The Hedgehog(Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development.Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 or 150 mg·kg^(-1) body weight at preselected time points between embryonic days(E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg·kg^(-1). Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death.
文摘Objective: To review and evaluate vismodegib, the first US Food and Drug Administration (FDA) approved treatment for locally advanced (laBCC) or metastatic basal cell carcinoma (mBCC) that has recurred after surgery or for patients in which surgery or radiation is not an option. Data Sources: A literature search using PubMed was conducted through January 2013, using the terms vismodegib, GDC-0449, and Erivedge. Additional literature was found through the reference citations of identified articles. Study Selection and Data Extraction: Potential sources were limited to human studies published in English with a priority placed on those focused on laBCC or mBCC. Data Synthesis: Vismodegib is a selective inhibitor of the hedgehog (Hh) pathway approved for the treatment of laBCC or mBCC that has recurred after surgery, or for patients for whom surgery or radiation is contraindicated. Vismodegib inhibits cancer cell growth and survival by binding Smoothened, a transmembrane protein involved in the Hedgehog signal transduction. Vismodegib is administered orally at a dose of 150 mg daily. It is primarily eliminated through the feces unchanged but does have some oxidative metabolites produced from the recombinant cytochrome P450 (CYP) 2C9 and CYP3A4/5. Despite CYP450 involvement, it appears to have very few drug interactions. The most common adverse events reported with vismodegib include muscle spasms, dysgeusia, alopecia, weight loss, fatigue, nausea, anorexia, and diarrhea. FDA approval was based on a single arm phase II study that demonstrated an objective response rate of 30% in mBCC patients and 45% in laBCC patients. Vismodegib was approved by the FDA on January 30, 2012 for use in patients with advanced basal cell carcinoma, and continues to be studied in other patient populations for additional potential uses. Conclusions: Based on a review of current evidence, vismodegib provides an effective and well-tolerated treatment for otherwise untreatable basal cell carcinoma.
