Despite aggressive therapy,glioblastoma(GBM)recurs in almost all patients and treatment options are very limited.Despite our growing understanding of how cellular transitions associate with relapse in GBM,critical gap...Despite aggressive therapy,glioblastoma(GBM)recurs in almost all patients and treatment options are very limited.Despite our growing understanding of how cellular transitions associate with relapse in GBM,critical gaps remain in our ability to block these molecular changes and treat recurrent disease.In this study we combine computational biology,forward-thinking understanding of miRNA biology and cutting-edge nucleic acid delivery vehicles to advance targeted therapeutics for GBM.Computational analysis of RNA sequencing from clinical GBM specimens identified TGFβ type Ⅱ receptor(TGFBR2)as a key player in the mesenchymal transition associated with worse outcome in GBM.Mechanistically,we show that elevated levels of TGFBR2 is conducive to reduced temozolomide(TMZ)sensitivity.This effect is,at least partially,induced by stem-cell driving events coordinated by the reprogramming transcription factors Oct4 and Sox2 that lead to open chromatin states.We show that blocking TGFBR2 via molecular and pharmacological approaches decreases stem cell capacity and sensitivity of clinical recurrent GBM(rGBM)isolates to TMZ in vitro.Network analysis uncovered miR-590-3p as a tumor suppressor that simultaneously inhibits multiple oncogenic nodes downstream of TGFBR2.We also developed novel biodegradable lipophilic poly(β-amino ester)nanoparticles(LiPBAEs)for in vivo microRNA(miRNAs)delivery.Following direct intra-tumoral infusion,these nanomiRs efficiently distribute through the tumors.Importantly,miR-590-3p nanomiRs inhibited the growth and extended survival of mice bearing orthotopic human rGBM xenografts,with an apparent 30% cure rate.These results show that miRNA-based targeted therapeutics provide new opportunities to treat rGBM and bypass the resistance to standard of care therapy.展开更多
基金supported by the United States NIH grants:R01NS073611(J.L.),R01NS096754(J.L.),R01CA228133(J.G.),P41EB028239(J.G.),R37CA246699(S.T.)and R01NS120949(H.L.B.)Summer Academic Research Experience and the Johns Hopkins Initiative for Careers in Science and Medicine(H.A.)+5 种基金Johns Hopkins University PURA(H.K.)Life Design Summer Experience Practicum(TC.T.and J.M.A)John Camp and Mindy Farber'74 Endowed Award(M.K.J.)and NCI F99 Fellowship F99CA284254(A.L.J.)The SKCCC(P30CA006973)Hugo W Moser institute IDDRC(5P50HD103538)Microscopy Core Grant(S10 OD016374).
文摘Despite aggressive therapy,glioblastoma(GBM)recurs in almost all patients and treatment options are very limited.Despite our growing understanding of how cellular transitions associate with relapse in GBM,critical gaps remain in our ability to block these molecular changes and treat recurrent disease.In this study we combine computational biology,forward-thinking understanding of miRNA biology and cutting-edge nucleic acid delivery vehicles to advance targeted therapeutics for GBM.Computational analysis of RNA sequencing from clinical GBM specimens identified TGFβ type Ⅱ receptor(TGFBR2)as a key player in the mesenchymal transition associated with worse outcome in GBM.Mechanistically,we show that elevated levels of TGFBR2 is conducive to reduced temozolomide(TMZ)sensitivity.This effect is,at least partially,induced by stem-cell driving events coordinated by the reprogramming transcription factors Oct4 and Sox2 that lead to open chromatin states.We show that blocking TGFBR2 via molecular and pharmacological approaches decreases stem cell capacity and sensitivity of clinical recurrent GBM(rGBM)isolates to TMZ in vitro.Network analysis uncovered miR-590-3p as a tumor suppressor that simultaneously inhibits multiple oncogenic nodes downstream of TGFBR2.We also developed novel biodegradable lipophilic poly(β-amino ester)nanoparticles(LiPBAEs)for in vivo microRNA(miRNAs)delivery.Following direct intra-tumoral infusion,these nanomiRs efficiently distribute through the tumors.Importantly,miR-590-3p nanomiRs inhibited the growth and extended survival of mice bearing orthotopic human rGBM xenografts,with an apparent 30% cure rate.These results show that miRNA-based targeted therapeutics provide new opportunities to treat rGBM and bypass the resistance to standard of care therapy.
