Duchenne Muscular Dystrophy (DMD) is a severe childhood form of muscular dystrophy. Both the severe form and its milder form of Becker Muscular Dystrophy (BMD) are caused by the mutation of dystrophin gene. Different ...Duchenne Muscular Dystrophy (DMD) is a severe childhood form of muscular dystrophy. Both the severe form and its milder form of Becker Muscular Dystrophy (BMD) are caused by the mutation of dystrophin gene. Different from some other genetic diseases such as hemophilia that can be treated by replacement therapy, there is no effective therapy for muscular dystrophy in conventional medication. Gene editing technology from the recently developed engineered nucleases such as TALENs has been successfully employed in genome modification of a variety of species, and will be applied in gene therapy of selected human diseases. The genetic basis of DMD and BMD indicates that DMD is a good target for gene therapy through returning the reading frame of dystrophin gene. Gene therapy strategies described here may apply to many other genetic diseases. Wider application of TALENs in gene therapy have the potential to dramatically prolong the lifespan of individuals with genetic diseases.展开更多
Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis.Up to date,even if patients at high risk of transformation can be identi...Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis.Up to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological transformation.Upregulation of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor simurosertib.CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen(MYC),implicated in stemness and histological transformation.Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of simurosertib.CDC7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma models.These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after transformation.As simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.展开更多
文摘Duchenne Muscular Dystrophy (DMD) is a severe childhood form of muscular dystrophy. Both the severe form and its milder form of Becker Muscular Dystrophy (BMD) are caused by the mutation of dystrophin gene. Different from some other genetic diseases such as hemophilia that can be treated by replacement therapy, there is no effective therapy for muscular dystrophy in conventional medication. Gene editing technology from the recently developed engineered nucleases such as TALENs has been successfully employed in genome modification of a variety of species, and will be applied in gene therapy of selected human diseases. The genetic basis of DMD and BMD indicates that DMD is a good target for gene therapy through returning the reading frame of dystrophin gene. Gene therapy strategies described here may apply to many other genetic diseases. Wider application of TALENs in gene therapy have the potential to dramatically prolong the lifespan of individuals with genetic diseases.
基金This study was supported by PO1 NIH PO1CA163227(Prostate Cancer Donor Program),NIH T32 CA1600001(to A.Q.V.),NCI R01 CA264078(to C.M.R.and,H.A.Y.)The Doris Duke Foundation(Grant 2021184)(to MCH),NCI P50 CA97186(to M.H.and C.M.),NCI R35 CA263816(to C.M.R.),NCI U24 CA213274(to C.M.R.),Yasuda Medical Foundation(to K.K.)+4 种基金the American Lung Association(to A.Q.V.)the Druckenmiller Center for Lung Cancer Research(to A.Q.V.,K.K.,and C.M.R.)This study was also supported by the Regional Ministry of Health and Consume of Andalucia RC-0004-2020(SMP)the Carlos II Health Institute through the projects"PI20/01109 and PI23/01679"(Co-funded by European Regional Development Fund/European Social Fund"A way to make Europe""nvesting in your future")(SMP).
文摘Neuroendocrine(NE)transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis.Up to date,even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53(TP53)and Retinoblastoma Transcriptional Corepressor 1(RB1)mutations in their tumors,no therapeutic strategies are available to prevent or delay histological transformation.Upregulation of the cell cycle kinase Cell Division Cycle 7(CDC7)occurred in tumors during the initial steps of NE transformation,already after TP53/RB1 co-inactivation,leading to induced sensitivity to the CDC7 inhibitor simurosertib.CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen(MYC),implicated in stemness and histological transformation.Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy,even in the presence of simurosertib.CDC7 inhibition also markedly extended response to standard cytotoxics(cisplatin,irinotecan)in lung and prostate small cell carcinoma models.These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity,as well as to effectively treat NE tumors de novo or after transformation.As simurosertib clinical efficacy trials are ongoing,this concept could be readily translated for patients at risk oftransformation.
