Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog–Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032
Giles W. Robinson,Brent A. Orr,Gang Wu,Sridharan Gururangan,Tong Lin,Ibrahim Qaddoumi,Roger J. Packer,Stewart Goldman,Michael D. Prados,Annick Desjardins,Murali Chintagumpala,Naoko Takebe,Sue C. Kaste,Michael Rusch,Sariah Allen,Arzu Onar-Thomas,Clinton F. Stewart,Maryam Fouladi,James M. Boyett,Richard J. Gilbertson,Tom Curran,David W. Ellison,Amar Gajjar +22 more
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TLDR
Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor and should be advanced in SHH-MB studies.Abstract:
Purpose Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). Patients and Methods Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. Results A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH–MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was...read more
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Journal ArticleDOI
Molecular Subgroups of Medulloblastoma: The Current Consensus
Michael D. Taylor,Paul A. Northcott,Andrey Korshunov,Marc Remke,Marc Remke,Yoon Jae Cho,Steven C. Clifford,Charles G. Eberhart,D. Williams Parsons,Stefan Rutkowski,Amar Gajjar,David W. Ellison,Peter Lichter,Richard J. Gilbertson,Scott L. Pomeroy,Marcel Kool,Stefan M. Pfister,Stefan M. Pfister +17 more
TL;DR: It is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, and herein is outlined the current consensus nomenclature, and the differences between the medullOBlastoma subgroups.
Journal ArticleDOI
Medulloblastoma Comprises Four Distinct Molecular Variants
Paul A. Northcott,Andrey Korshunov,Hendrik Witt,Thomas Hielscher,Charles G. Eberhart,Stephen C. Mack,Eric Bouffet,Steven C. Clifford,Cynthia Hawkins,Pim J. French,James T. Rutka,Stefan M. Pfister,Michael D. Taylor +12 more
TL;DR: The authors' integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome.
Journal ArticleDOI
Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449
Charles M. Rudin,Christine L. Hann,John Laterra,Robert L. Yauch,Christopher A. Callahan,Ling Fu,Thomas Holcomb,Jeremy Stinson,Stephen E. Gould,Barbara Coleman,Patricia LoRusso,Daniel D. Von Hoff,Frederic J. de Sauvage,Jennifer A. Low +13 more
TL;DR: A 26-year-old man with metastatic medulloblastoma that was refractory to multiple therapies was treated with a novel hedgehog pathway inhibitor, GDC-0449; treatment resulted in rapid (although transient) regression of the tumor and reduction of symptoms.
Journal ArticleDOI
Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma
Robert L. Yauch,Gerrit J. P. Dijkgraaf,Bruno Alicke,Thomas Januario,Christina P. Ahn,Thomas Holcomb,Kanan Pujara,Jeremy Stinson,Christopher A. Callahan,Tracy Tang,J. Fernando Bazan,Zhengyan Kan,Somasekar Seshagiri,Christine L. Hann,Stephen E. Gould,Jennifer A. Low,Charles M. Rudin,Frederic J. de Sauvage +17 more
TL;DR: These findings show that acquired mutations in a serpentine receptor with features of a G protein–coupled receptor can serve as a mechanism of drug resistance in human cancer.
Journal ArticleDOI
Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas
Marcel Kool,Andrey Korshunov,Marc Remke,Marc Remke,David T.W. Jones,Maria Schlanstein,Paul A. Northcott,Yoon Jae Cho,Jan Koster,Antoinette Y N Schouten-van Meeteren,Dannis G. van Vuurden,Steven C. Clifford,Torsten Pietsch,André O. von Bueren,Stefan Rutkowski,Martin G. McCabe,Martin G. McCabe,V. Peter Collins,Magnus Bäcklund,Christine Haberler,Franck Bourdeaut,Olivier Delattre,François Doz,David W. Ellison,Richard J. Gilbertson,Scott L. Pomeroy,Michael D. Taylor,Peter Lichter,Stefan M. Pfister,Stefan M. Pfister +29 more
TL;DR: A meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies shows how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival.
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