Nevoid Basal Cell Carcinoma (Gorlin) Syndrome

Gorlin, Robert J.

doi:10.1007/978-3-211-69500-5_45

Cited by 1 publication

(1 citation statement)

References 238 publications

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“…Hedgehog (Hh) proteins are well-known to be overexpressed in paediatric medulloblastoma 1 . Mutations that occur in the family of Hh-pathway genes such as patched-1, suppressor of fuse and smoothened leads to an increased level of the glioma-associated oncogene (Gli1), a downstream transcription factor of Hh 2 . In the clinic, hedgehog inhibitors are used to decrease the Hh-activity and thereby impede tumor progression 3 – 5 .…”

Section: Introductionmentioning

confidence: 99%

Radial shock waves prevent growth retardation caused by the clinically used drug vismodegib in ex vivo cultured bones

Ramesh

Sävendahl

Madhuri

et al. 2020

Sci Rep

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In childhood medulloblastoma patients, the hedgehog antagonist vismodegib is an effective anticancer treatment but unfortunately induces irreversible growth arrests and growth impairment limiting its use in skeletally immature patients. We hypothesized that radial shock wave treatment (rSWT) may protect drug-induced growth impairment owing to its osteogenic effects. Fetal rat metatarsal bones were exposed to vismodegib (day 0-5; 100 nM) and/or rSWT (single session); other bones from day 1 were continuously exposed to a Gli1 antagonist (GANT61; 10 µM) and/or rSWT (single session). Control bones were untreated. The bone length was measured at intervals; histomorphometric analysis and immunostaining for PCNA, Gli1, and Ihh were performed on the sectioned bones. Bones treated with vismodegib showed impaired bone growth, reduced height of the resting-proliferative zone and reduced hypertrophic cell size compared to control. In vismodegib treated bones, a single session of rSWT partially rescued bone growth, increased the growth velocity, hypertrophic cell size, and restored growth plate morphology. Bones exposed to GANT61 showed impaired bone growth and disorganized growth plate while when combined with rSWT these effects were partially prevented. Locally applied rSWT had a chondroprotective effect in rat metatarsal bones and suggest a novel strategy to prevent growth impairment caused by vismodegib. Hedgehog (Hh) proteins are well-known to be overexpressed in paediatric medulloblastoma 1. Mutations that occur in the family of Hh-pathway genes such as patched-1, suppressor of fuse and smoothened leads to an increased level of the glioma-associated oncogene (Gli1), a downstream transcription factor of Hh 2. In the clinic, hedgehog inhibitors are used to decrease the Hh-activity and thereby impede tumor progression 3-5. However, stable expression of the Hh-gene is essential to maintain chondrocyte proliferation and hypertrophy during bone growth 6. A recent study reported that prolonged exposure to vismodegib, a Hh-antagonist, in children with medulloblastoma resulted in irreversible growth plate fusion causing growth arrest of long bones 7,8. Preclinical studies in young mice exposed to a Hh-antagonist also showed growth arrests and bone growth defects 9. Mechanistic studies revealed that even brief exposure to a Hh-inhibitor was enough to damage the growth plates by diminishing the numbers of reserve and proliferative chondrocytes 9. These findings further imply that it may not be possible to arrive at a dose that selectively targets tumor growth with no side-effects on bone development. Therefore, in children, a protective strategy for growth plate shielding without interfering with the desired anticancer effects of vismodegib in the neural tissue is highly desired. In vitro studies using cultured rat metatarsal bones 10 and in vivo studies in rabbits 11 and humans 12 have shown that radial shock wave treatment (rSWT), a non-invasive modality used in the clinic, have stimulatory effects on bone growth 10. Furthermore...

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