Thursday, April 17, 2014
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Markers of distinct sonic
hedgehog homolog (SHH)-driven
Mouse and sequencing
studies suggest SHH-driven medulloblastomas in adults, children and infants
are molecularly distinct from one another and should be treated using
different protocols. Most adults but only about half of pediatric patients
with SHH-driven medulloblastomas respond to smoothened
inhibitors. In SHH-driven medulloblastoma tumor samples from 50 adults, 33
children over 3 years old and 50 infants, sequencing showed that SMO
mutations were enriched in adults, suppressor
of fused homolog (SUFU)
mutations were found almost exclusively in infants and amplifications in both
myelocytomatosis viral related oncogene neuroblastoma derived
oncogene homolog 2 zinc finger protein (GLI2)
mutations were enriched in children. In mouse xenograft models, SUFU-mutated
and MYCN-amplified SHH-driven medulloblastomas showed resistance to
the small molecule SMO inhibitor LDE225.
Next steps could include developing a patient screening assay for the gene
Novartis AG has
LDE225 in Phase III testing to treat basal cell carcinoma (BCC) and Phase I
testing to treat other cancers.
Roche's Genentech Inc.
unit markets the SMO inhibitor Erivedge
to treat BCC.
At least four other companies have SMO inhibitors in Phase III or earlier
testing to treat various cancers.
Published online April 17, 2014
Patent and licensing status
Kool, M. et al. Cancer
Cell; published online March 17, 2014;
Contact: Marcel Kool, German Cancer Research Center, Heidelberg,
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