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• W205294904 endingPage "1104" @default.
• W205294904 startingPage "1077" @default.
• W205294904 abstract "Medulloblastoma (MB) therapy—resection, chemotherapy, and radiation—results in admirable survival rates (70–85% 5-year survival of medium- to high-risk cases) but unacceptable chronic toxicities, including endocrine dysfunction and cognitive impairment. The limited efficacy of the current therapeutic regimen may be linked to the recently discovered MB cancer stem cells, which may regenerate tumors after bulk mass reduction. Nonetheless, the discovery of tumor stem cells as a new target has suggested a potential new approach for improving upon conventional cytotoxic chemotherapy. Differentiation agents that would specifically target tumor stem cells without being universally cytotoxic to proliferating cells could reduce systemic toxicity as well as deplete cell populations responsible for tumor maintenance. All-trans retinoic acid (ATRA) is the first and only differentiation agent that has proven effective in the clinical setting, inducing a 90% remission rate of acute promyelocytic leukemia (APL) when used as adjuvant to chemotherapy. Retinoids have also proven effective against a large fraction of MB cell lines and primary tumors. MB is an embryonal tumor that, like APL, relies upon the circumvention of endogenous differentiation pathways for tumorigenesis. Retinoid resistance in some MB cell lines has hindered its development as a universally applicable therapeutic. It has been shown that retinoid-resistant cell lines can be responsive to downstream targets of retinoid activity, suggesting that retinoid resistance occurs via disruption of upstream components of the pathway. Functional intermediates of retinoid activity have been identified; however, the ultimate targets of such intermediates remain elusive. Some studies have shown that retinoids exert their antitumor effect against MB in part by inducing Bmp2 production and subsequent activation of the TGFβ pathway. Other studies have demonstrated that ATRA silences the OTX2 oncogene, whose expression correlates with ATRA responsiveness of MB cell lines. Alternative pathways accounting for the full effect of retinoids against MB (independent of Bmp2 and OTX2) as well as final targets of known pathways have yet to be identified. Delineation of the pathways through which ATRA exerts its pleiotropic effects could reveal potential therapeutic targets that recapitulate differentiation or apoptosis in both retinoid-sensitive and retinoid-resistant cell lines and thus serve as a more broadly applicable therapy." @default.
• W205294904 created "2016-06-24" @default.
• W205294904 creator A5034933958 @default.
• W205294904 creator A5070239634 @default.
• W205294904 date "2009-01-01" @default.
• W205294904 modified "2023-09-23" @default.
• W205294904 title "The Use of Retinoids as Differentiation Agents Against Medulloblastoma" @default.
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