Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts

Zhai, Jiemei; Zhang, Heyu; Zhang, Jianyun; Zhang, Ran; Hong, Yu; Qu, Jingwei; Chen, Feng; Li, Tiejun

doi:10.1038/s41368-018-0034-x

Cited by 17 publications

(14 citation statements)

References 41 publications

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“…Mutated pathogenic PTCH1 protein p.R135X and p.V403W were previously described. 31 Patient #3 had a frameshift germline mutation resulting in a nonfunctional PTCH1 protein, which is concordant with the clinical observation of a Gorlin syndrome. Patient #8 had a somatic and germline missense mutation c.787G>A.…”

Section: Resultssupporting

confidence: 71%

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Pereira

Torrejón

Kariyawasam

et al. 2021

Neuro-Oncology Advances

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Background Smoothened inhibitors (SMOi) have shown activity in Sonic Hedgehog (SHH) medulloblastoma, however this therapeutic class was not developed in children due to severe effects reported on growth. We hereby report long-term follow up of young patients treated with SMOi for recurrent medulloblastoma. Methods Clinical data on response and toxicity from patients treated with vismodegib or sonidegib from 2011 to 2019 for a SHH medulloblastoma were retrospectively reviewed. Methylation analysis and whole exome sequencing were performed whenever possible. Results All patients with a somatic PTCH1 mutation responded to SMOi (6/8), including two prolonged complete responses. One patient was free of disease 8.2 years after treatment. SMOi was challenged again for three patients. Two of them had a response, one with SMOi alone, the other one in combination with temozolomide despite previous progression under monotherapy. SMO resistance mutations were found in patients from biopsy at relapse. Combination with temozolomide or surgery plus radiotherapy was associated with very long disease control in two patients. The most severe adverse events were myalgia and growth plate fusion with metaphyseal sclerosis. Normal growth velocity was recovered for one patient although her final height was below estimated target height. Conclusion Targeting SMO in mutated PTCH1 is an interesting strategy for long-term responses. Combination of SMOi with chemotherapy or surgery and local radiotherapy is an appealing strategy to prevent early resistance and diminish SMOi exposure, especially in young patients. Inhibition of SHH pathway causes growth and development impairment but partial recovery of the growth velocity is possible.

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Section: Resultssupporting

confidence: 71%

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Pereira

Torrejón

Kariyawasam

et al. 2021

Neuro-Oncology Advances

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“…There are many reasons due to which it is declared as a separate cyst such as lack of palisading, less aggressive behavior and less recurrent rate, 21 however still controversy exists. 22…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical expression of ki-67 in odontogenic keratocyst: Evidence of aggressive behavior.

Saif

Jehangir²,

Nagi

et al. 2020

TPMJ

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The odontogenic keratocyst (OKC) well-known for its aggressiveness and high recurrence rate, comprises approximately 11% of all jaw cysts. Due to its aggressive behavior it was placed into category of tumour in 2005 by the World Health Organization (WHO). Objectives: The purpose of this study was to determine the Ki-67 expression in Odontogenic Keratocysts to predict its proliferative potential. Study Design: Descriptive study. Setting: Department of Morbid Anatomy and Histopathology, UHS. Periods: June 2014- June 2018. Material & Methods: This is a descriptive study comprising of 39 cases of odontogenic cysts. These surgically removed samples were processed at University of Health Sciences (UHS) laboratory. Routine staining with Hematoxylin & Eosin stain along with immunohistochemistry (IHC) with Ki-67 antibody was performed. Immunohisto chemical scoring was done on the basis of percentage of the nuclear staining of Ki-67. Data was entered into SPSS 22 and descriptive statistics were measured in the form of percentage and frequency. Quantitative variables such as age of patient, size of the cyst, and Ki-67 score were also measured. P value <0.05 was taken as significant. Results: The mean age of the patients was 25.08 ±14.5 years. Significant association was observed between histological variables with odontogenic keratocyst such as parakeratinized epithelial lining (p = 0.00), epithelial hyperplasia both typical and atypical (p = 0.02) and focal spongiosis (p = 0.04). Foci having epithelial atypia demonstrated stronger staining intensity compared to adjacent normal epithelium. However, no significant association was observed between the histological variables and Ki-67 expression. Conclusion: OKC expressed low Ki-67 expression in most of the cases, however, foci of strong expression were also observed in few cases.

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“…[53][54][55] The role of monoallelic PTCH1 inactivation has been supported by in vivo studies. [56][57][58] BCC, medulloblastoma, and rhabdomyosarcoma, like KCOT, may all occur sporadically or in the context of NBCCS.…”

Section: Discussionmentioning

confidence: 99%

Biallelic PTCH1 Inactivation Is a Dominant Genomic Change in Sporadic Keratocystic Odontogenic Tumors

Stojanov

Schaefer

Menon

et al. 2019

American Journal of Surgical Pathology

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Keratocystic odontogenic tumors (KCOTs) are locally aggressive odontogenic neoplasms with recurrence rates of up to 60%. Approximately 5% of KCOTs are associated with nevoid basal cell carcinoma (Gorlin) syndrome and 90% of these show genomic inactivation of the PTCH1 gene encoding Patched 1. Sporadic KCOTs reportedly have PTCH1 mutations in 30% of cases, but previous genomic analyses have been limited by low tumor DNA yield. The aim of this study was to identify recurrent genomic aberrations in sporadic KCOTs using a next-generation sequencing panel with complete exonic coverage of sonic hedgehog (SHH) pathway members PTCH1, SMO, SUFU, GLI1, and GLI2. Included were 44 sporadic KCOTs from 23 female and 21 male patients with a median age of 50 years (range, 10 to 82 y) and located in the mandible (N = 33) or maxilla (N = 11). Sequencing identified PTCH1 inactivating mutations in 41/44 (93%) cases, with biallelic inactivation in 35 (80%) cases; 9q copy neutral loss of heterozygosity targeting the PTCH1 locus was identified in 15 (34%) cases. No genomic aberrations were identified in other sequenced SHH pathway members. In summary, we demonstrate PTCH1 inactivating mutations in 93% of sporadic KCOTs, indicating that SHH pathway alterations are a near-universal event in these benign but

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Effect of the sonic hedgehog inhibitor GDC-0449 on an in vitro isogenic cellular model simulating odontogenic keratocysts

Cited by 17 publications

References 41 publications

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Clinical and molecular analysis of smoothened inhibitors in Sonic Hedgehog medulloblastoma

Immunohistochemical expression of ki-67 in odontogenic keratocyst: Evidence of aggressive behavior.

Biallelic PTCH1 Inactivation Is a Dominant Genomic Change in Sporadic Keratocystic Odontogenic Tumors

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