Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib

Lou, Emil; Schomaker, Matthew; Wilson, Jon D.; Ahrens, Mary; Dolan, Michelle; Nelson, Andrew C.

doi:10.1080/15384047.2016.1220453

Cited by 22 publications

(14 citation statements)

References 21 publications

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“…2). Importantly, PTCH1 oncogenic mutations are described as actionable gene mutations for SMO-inhibitors vismodegig and sonidegib (in clinical trials for recurrent or refractory MB showing encouraging results) [31][32][33][34] . It is also important to highlight the CNV landscape (Fig.…”

Section: Resultsmentioning

confidence: 99%

Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma

et al. 2020

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The molecular characterisation of medulloblastoma, the most common paediatric brain tumour, is crucial for the correct management and treatment of this heterogenous disease. However, insufficient tissue sample, the presence of tumour heterogeneity, or disseminated disease can challenge its diagnosis and monitoring. Here, we report that the cerebrospinal fluid (CSF) circulating tumour DNA (ctDNA) recapitulates the genomic alterations of the tumour and facilitates subgrouping and risk stratification, providing valuable information about diagnosis and prognosis. CSF ctDNA also characterises the intra-tumour genomic heterogeneity identifying small subclones. ctDNA is abundant in the CSF but barely present in plasma and longitudinal analysis of CSF ctDNA allows the study of minimal residual disease, genomic evolution and the characterisation of tumours at recurrence. Ultimately, CSF ctDNA analysis could facilitate the clinical management of medulloblastoma patients and help the design of tailored therapeutic strategies, increasing treatment efficacy while reducing excessive treatment to prevent long-term secondary effects.

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Section: Resultsmentioning

confidence: 99%

Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma

et al. 2020

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“…Only five recent patients had molecular testing: 1 WNT, 2 SHH (1 TP53 wild-type, 1 TP53 mutated) and 2 non-WNT/non-SHH. SHH-pathway inhibitors are currently being evaluated in phase I–III trials, and may provide a therapeutic option to chemoradiation protocols currently used for these patients [7, 44]. Despite advances in subtyping, it remains difficult to assess prognosis in adult MB since studies have reported heterogenous treatment, many without chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Long-term outcomes of adult medulloblastoma patients treated with radiotherapy

Beal

Braganca

et al. 2017

J Neurooncol

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Medulloblastoma (MB) is rare in adults and treatment guidelines are consequently not well-established. Few modern series have reported long-term follow-up and treatment sequelae. We examined long-term outcomes of adult MB patients at one institution. Records of 29 consecutive patients (18 male, 11 female) aged ≥ 18 years who received radiotherapy (RT) for primary MB from 1990 to 2016 were reviewed. Median age at diagnosis was 28 years (range 18-72 years). Seventeen patients were standard risk and 12 were high risk. Nineteen patients had gross total resection, seven had subtotal resection, and three had biopsy only. Median craniospinal irradiation and boost doses were 36 Gy (range 23.4-39.6 Gy) and 55.8 Gy (range 54-59.4 Gy), respectively. Of 24 patients receiving chemotherapy, 20 received concurrent + adjuvant and 4 received adjuvant only. At median follow-up of 9.0 years (range 1.1-20.5 years), five patients recurred: four in the posterior fossa and one in both the posterior fossa and above the tentorium. Five patients died: two of disease progression and three after possible treatment complications (seizure, lobar pneumonia, and multifactorial sepsis). At last follow-up, 23 patients were alive with no evidence of disease. Long-term effects include executive dysfunction (n = 17), weakness/ataxia (n = 16), and depression/anxiety (n = 13). Kaplan-Meier estimates of 10-year overall survival and failure-free survival are 83% (95% confidence interval [CI] 59-93%) and 79% (CI 55-91%), respectively. Despite encouraging disease control in this cohort, long-term sequelae may limit quality of life. Multimodality pediatric regimens using lower RT doses may be considered to reduce treatment-related morbidity.

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“…Thus far, there are many Smo inhibitors have been under investigation in clinical trials. Among them, GDC-0449 (vismodegib) was approved by FDA for treatment of advanced BCC in 2012 (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Identification of a Potent Antagonist of Smoothened in Hedgehog Signaling

Fan

Zhao

et al. 2020

Preprint

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Background Hedgehog signaling is essential to the regulation of embryonic development, tissue homeostasis, and stem cell self-renewal, making it a prime target for developing cancer therapeutics. Given the close link between aberrant Hedgehog signaling and cancers, many small molecular compounds have been developed to inhibit this pathway for treating cancer and several of such compounds have been approved by FDA (GDC-0449 and LDE-225). As we known, acquired drug resistance is the main obstacle of first generation of Smoothened inhibitors. Therefore, new Smoothened inhibitors that could inhibit wild-type and mutant receptors are essential for refractory cancers. ResultsWe established the Smoothened β arrestin 2 GFP high throughput screening platform based on the mechanistic discovery of Hedgehog signaling pathway, and discovered several active small molecules targeting Smoothened including 0025A 0025A. Here we show that 0025A can block the translocation of β arrestin 2 GFP to Smoothened , displace Bodipycyclopamine binding to wild type Smoothened or mutant Smoothened D473H and reduce the expression of Gli upon Hedgehog stimulation. In addition, we reveal that 0025A can effectively suppress hair follicle morphogenesis and hair growth in mice. Conclusions Thus, our results demonstrate that 0025A is a potent antagonist targeting Smoothened wild-type and mutant type and mutant receptors in the Hreceptors signaling pathway and may provide a new new therapy for refractory cancers.

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Complete and sustained response of adult medulloblastoma to first-line sonic hedgehog inhibition with vismodegib

Cited by 22 publications

References 21 publications

Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma

Circulating tumour DNA from the cerebrospinal fluid allows the characterisation and monitoring of medulloblastoma

Long-term outcomes of adult medulloblastoma patients treated with radiotherapy

Identification of a Potent Antagonist of Smoothened in Hedgehog Signaling

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