Treatment of medulloblastoma in young children

Walker, David; Wilne, Sophie

doi:10.1016/s1470-2045(05)70259-x

Cited by 9 publications

(4 citation statements)

References 7 publications

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“…State of the art treatment combines surgery, craniospinal irradiation, and multiple chemotherapeutics with severe sequelae of toxic side effects (2)(3)(4). The development of novel treatment options is therefore urgently needed.…”

Section: Introductionmentioning

confidence: 99%

Sox2 Requirement in Sonic Hedgehog-Associated Medulloblastoma

et al. 2013

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The transcription factor Sox2 has been shown to play essential roles during embryonic development as well as in cancer. To more precisely understand tumor biology and to identify potential therapeutical targets, we thoroughly investigated the expression and function of Sox2 in medulloblastoma, a malignant embryonic brain tumor that initiates in the posterior fossa and eventually spreads throughout the entire cerebrospinal axis. We examined a large series of tumor samples (n ¼ 188) to show that SOX2 is specifically expressed in Sonic hedgehog (SHH)-associated medulloblastoma with an interesting preponderance in adolescent and adult cases. We further show that cerebellar granule neuron precursors (CGNP), which are believed to serve as the cell of origin for this medulloblastoma subgroup, express Sox2 in early stages. Also, Shh-associated medulloblastoma can be initiated from such Sox2-positive CGNPs in mice. Independent of their endogenous Sox2 expression, constitutive activation of Shh signaling in CGNPs resulted in significantly enhanced proliferation and ectopic expression of Sox2 in vitro and Sox2-positive medulloblastoma in vivo. Genetic ablation of Sox2 from murine medulloblastoma did not affect survival, most likely due to a compensatory overexpression of Sox3. However, acute deletion of Sox2 from primary cultures of CGNPs with constitutive Shh signaling significantly decreased proliferation, whereas overexpression of Sox2 enhanced proliferation of murine medulloblastoma cells. We conclude that Sox2 is a marker for Shhdependent medulloblastomas where it is required and sufficient to drive tumor cell proliferation. Cancer Res; 73(12); 3796-807. Ó2013 AACR.

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Section: Introductionmentioning

confidence: 99%

Sox2 Requirement in Sonic Hedgehog-Associated Medulloblastoma

et al. 2013

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“…It is difficult to treat because tumor cells invade the surrounding normal tissue and disseminate through the cerebral spinal fluid, leading to metastasis throughout the cerebral spinal axis. Intensive multimodality treatment that combines surgery, craniospinal irradiation, and multiple drug chemotherapy can achieve long-term survival rates of 50% to 70%, but at significant cost due to toxic side effects (1)(2)(3). Most medulloblastoma survivors suffer long-term treatment-related morbidity that greatly affects their quality of life (1,2).…”

Section: Introductionmentioning

confidence: 99%

“…Intensive multimodality treatment that combines surgery, craniospinal irradiation, and multiple drug chemotherapy can achieve long-term survival rates of 50% to 70%, but at significant cost due to toxic side effects (1)(2)(3). Most medulloblastoma survivors suffer long-term treatment-related morbidity that greatly affects their quality of life (1,2). New therapeutic approaches with superior efficacy and reduced toxicity are urgently needed in the clinical management of children with medulloblastoma (3,4).…”

Section: Introductionmentioning

confidence: 99%

Targeting Human Medulloblastoma: Oncolytic Virotherapy with Myxoma Virus Is Enhanced by Rapamycin

et al. 2007

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We have shown previously the oncolytic potential of myxoma virus in a murine xenograft model of human glioma. Here, we show that myxoma virus used alone or in combination with rapamycin is effective and safe when used in experimental models of medulloblastoma in vitro and in vivo. Nine of 10 medulloblastoma cell lines tested were susceptible to lethal myxoma virus infection, and pretreatment of cells with rapamycin increased the extent of in vitro oncolysis. Intratumoral injection of live myxoma virus when compared with control inactivated virus prolonged survival in D341 and Daoy orthotopic human medulloblastoma xenograft mouse models [D341 median survival: 21 versus 12.5 days; P = 0.0008; Daoy median survival: not reached (three of five mice apparently ''cured'' after 223 days) versus 75 days; P = 0.0021]. Rapamycin increased the extent of viral oncolysis, ''curing'' most Daoy tumor-bearing mice and reducing or eliminating spinal cord and ventricle metastases. Rapamycin enhanced tumor-specific myxoma virus replication in vivo and prolonged survival of D341 tumor-bearing mice (median survival of mice treated with live virus (LV) and rapamycin, versus LV alone, versus rapamycin alone, versus inactivated virus: 25 days versus 19, 13, and 11 days, respectively; P < 0.0001). Rapamycin increased the levels of constitutively activated Akt in Daoy and D341 cells, which may explain its ability to enhance myxoma virus oncolysis. These observations suggest that myxoma virus may be an effective oncolytic agent against medulloblastoma and that combination therapy with signaling inhibitors that modulate activity of the phosphatidylinositol 3-kinase/Akt pathway will further enhance the oncolytic potential of myxoma virus.

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“…Rutkowski reported very high survival rates in pre-school children treated with chemotherapy-only strategy including intraventricular methotrexate [109]. The proposal that intrathecal therapy be tested in a prospective European trial of medulloblastoma in this young age group is currently the focus of debate [139].…”

Section: Introductionmentioning

confidence: 99%