Classic and desmoplastic medulloblastoma: Complete case reports and characterizations of two new cell lines

Holthouse, David; Dallas, Peter B.; Ford, Jette; Fabian, V.; Murch, Ashleigh; Watson, Marcia; Wong, Gary K. W.; Bertram, Cornelia M.; Egli, Simone; Baker, David L.; Kees, Ursula R.

doi:10.1111/j.1440-1789.2008.00989.x

Cited by 10 publications

(6 citation statements)

References 48 publications

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“…Literature data further indicate that although Wnt tumors are classic MB, and most Hh tumors are desmoplastic MB, the Wnt and Hh subgroups always cluster together, suggesting they are biologically similar [11]. Moreover a number of gene targets of the Wnt pathway are found to be up-regulated in desmoplastic relative to classic MB cell lines, consistent with aberrant activation of Wnt pathway in desmoplastic MB, thus definitely implying a Wnt-driven role in these tumors [12,13].…”

Section: Introductionmentioning

confidence: 59%

Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/β-catenin signaling

Cimmino¹,

Scoppettuolo²,

Carotenuto³

et al. 2011

J Neurooncol

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Medulloblastoma is one of the leading causes of morbidity and mortality in pediatric cancer. Wnt-active tumors, an independent molecular subgroup in medulloblastoma, are characterized by a distinct pattern of genomic aberrations. We assessed the anticancer activity of cantharidin and norcantharidin against medulloblastoma, as cell lines in vitro and in athymic nude mice in vivo. Cantharidin and norcantharidin treatment impaired the growth of DAOY and UW228 medulloblastoma cells and promoted the loss of β-catenin activation and the β-catenin nuclearization linked to N-cadherin impairment in vitro. Intra-peritoneal administration of norcantharidin inhibited the growth of intra-cerebellum tumors in orthotopic xenograft nude mice. Analysis of the xenograft tissues revealed enhanced neuronal differentiation and reduced β-catenin expression. Our findings suggest that norcantharidin has potential therapeutic applications in the treatment of medulloblastoma as a result of its ability to cross the blood-brain barrier and its impairment of Wnt-β-catenin signaling.

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Section: Introductionmentioning

confidence: 59%

Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/β-catenin signaling

Cimmino¹,

Scoppettuolo²,

Carotenuto³

et al. 2011

J Neurooncol

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“…To confirm these findings in an additional medulloblastoma mouse model, we studied dacomitinib in ERBB2-expressing PER547 medulloblastoma cells [38] . Similar to Daoy medulloblastoma cells, dacomitinib was observed to behave antagonistically with cisplatin in vitro , and was only additive with 4HPC.…”

Section: Resultsmentioning

confidence: 80%

A Pre-Clinical Assessment of the Pan-ERBB Inhibitor Dacomitinib in Pediatric and Adult Brain Tumors

et al. 2018

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Glioblastoma in adults, and medulloblastoma and pineoblastoma that mainly affect children, are aggressive brain tumors. The survival for patients with glioblastoma remains dismal. While the cure rate for medulloblastoma exceeds 70%, this figure has stagnated over the past few decades and survivors still contend with significant long-term debilitating side effects. The prognosis for pineoblastoma is age-dependent, with little chance of a cure for children younger than three years. More effective molecularly targeted strategies are urgently required to treat these cancers. Hyper-activation of epidermal growth factor receptor (EGFR) signaling is characteristic of several different classes of human cancers, including a subset of glioblastoma and medulloblastoma. This has provided the impetus for the development of a suite of EGFR pathway blockers, including second generation irreversible inhibitors, such as dacomitinib. We have developed a comprehensive drug evaluation pipeline, including in vitro interaction analyses and orthotopic xenograft mouse models, to address the efficacy of drugs for brain tumor treatment, enabling the exclusion of potentially ineffective treatments and prioritization of truly beneficial novel treatments for clinical trial. We used this system to examine the effects of dacomitinib as a single agent, or in combination with conventional chemotherapeutics, on the growth of human adult and pediatric brain tumor cell lines. Dacomitinib inhibited EGFR or EGFRvIII activity in vitro in all three tumor types tested, and as a single agent induced a modest increase in survival time for mice bearing glioblastoma, which accurately predicted human clinical trial data. For pediatric medulloblastoma, dacomitinib blocked EGFR/HER signalling in orthotopic xenografts and extended median survival as a single agent, however was antagonistic when used in combination with standard frontline medulloblastoma chemotherapies. The findings caution against the use of dacomitinib for pediatric brain tumor clinical trials.

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“…Clinically, histology it also an important prognostic factor, whereas patients with anaplastic histology have an inferior outcome compared to patients with desmoplastic and classic histology (42, 43). Interestingly, while our analyses revealed REST levels to be increased in all histological sub types of medulloblastoma, there was an interesting and unexpected trend wherein 3 of the 7 patients with desmoplastic tumors that exhibited high REST protein (++++) staining also had the worst outcome.…”

Section: Discussionmentioning

confidence: 99%

REST Is a Novel Prognostic Factor and Therapeutic Target for Medulloblastoma

Taylor

Fangusaro

Rajaram

et al. 2012

Molecular Cancer Therapeutics

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Medulloblastoma is a malignant pediatric brain tumor. Current treatment following patient stratification into standard and high-risk groups using clinical features, has improved survival. However, a subset of patients with standard-risk features have unanticipated aggressive disease, underscoring the need for a better understanding of tumor biology and development of novel treatments. Poor differentiation, a hallmark of medulloblastomas is associated with elevated expression levels of the repressor of neuronal differentiation REST. Here, we assessed if elevated REST expression levels had prognostic significance and if its pharmacological manipulation would promote neurogenesis and block tumor cell growth. REST levels in patient tumors were measured by immunohistochemistry (IHC) and stratified into low/moderate- (+/++/+++) and high-REST (+++++) groups. Kaplan-Meier curves revealed that patients with high-REST tumors had worse overall and event-free survival compared to patients with REST-negative or REST-low tumors. Since histone deacetylases (HDACs), are required for REST-dependent repression of neurogenesis, we evaluated a panel of HDAC inhibitors (HDACIs) for their effects on growth and differentiation of established and primary REST-positive cell lines. MS-275, trichostatin-A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) upregulated expression of the REST-target neuronal differentiation gene, Syn1, suggesting a potential effect of these HDACIs on REST function. Interestingly, VPA and TSA substantially increased histone acetylation at the REST promoter and activated its transcription, whereas SAHA unexpectedly promoted its proteasomal degradation. A REST-dependent decrease in cell growth was also observed following SAHA treatment. Thus, our studies suggest that HDACIs may have therapeutic potential for patients with REST-positive tumors. This warrants further investigation.

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Classic and desmoplastic medulloblastoma: Complete case reports and characterizations of two new cell lines

Cited by 10 publications

References 48 publications

Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/β-catenin signaling

Norcantharidin impairs medulloblastoma growth by inhibition of Wnt/β-catenin signaling

A Pre-Clinical Assessment of the Pan-ERBB Inhibitor Dacomitinib in Pediatric and Adult Brain Tumors

REST Is a Novel Prognostic Factor and Therapeutic Target for Medulloblastoma

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