Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription...Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription,RNA splicing,and protein synthesis.Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers,rendering cyclins and CDKs attractive therapeutic targets.Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use,fueling the development of CDK-targeted therapies.With this enthusiasm for finding novel CDK-targeting anti-cancer agents,there have also been exciting advances in the field of targeted protein degradation through innovative strategies,such as using proteolysis-targeting chimera,heat shock protein 90(HSP90)-mediated targeting chimera,hydrophobic tag-based protein degradation,and molecular glue.With a focus on the translational potential of cyclin-and CDK-targeting strategies in cancer,this review presents the fundamental roles of cyclins and CDKs in cancer.Furthermore,it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs,detailing the underlying mechanisms of action for each approach.A comprehensive overview of the structure and activity of existing CDK degraders is also provided.By examining the structure‒activity relationships,target profiles,and biological effects of reported cyclin/CDK degraders,this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.展开更多
Background Pediatric gliomas are the most frequently occurring central nervous system tumors in children.While targeted therapies have been widely applied in the treatment of many adult cancers,their use in pediatric ...Background Pediatric gliomas are the most frequently occurring central nervous system tumors in children.While targeted therapies have been widely applied in the treatment of many adult cancers,their use in pediatric gliomas has lagged behind.However,recent advances in multiomics profiling of pediatric gliomas,coupled with the approval of inhibitors against Raf serine/threonine kinase(RAF),isocitrate dehydrogenase 1/2(IDH1/2)and neurotrophic receptor tyrosine kinase(NTRK),have spurred significant progress in this field.In light of these developments,this review aims to provide a comprehensive overview of current advancements and the evolving landscape of targeted therapeutic strategies and approaches for pediatric gliomas.Data sources Data analyzed in this study were obtained from the literature from PubMed,as well as other online databases and websites,including ClinicalTrials.gov and the Pediatric Neuro-Oncology Consortium.Results Based on findings from multiomics profiling,significant insights have been gained into the genetic and molecular landscape of pediatric gliomas,enabling the identification of key mutations and potentially targetable lesions.These advancements provide rationales for the development of more precise treatment strategies and targeted therapies.Recent approvals of targeted therapies and ongoing clinical trials in pediatric gliomas are converging on the targeting of key signaling molecules and metabolic pathways.Conclusions In the molecular era,targeted therapies offer new hope for more effective and personalized treatment options for pediatric glioma patients.By developing and tailoring treatments to target specific molecular and metabolic vulnerabilities,targeted therapies have the potential to improve the clinical management of pediatric gliomas,ultimately enhancing both the treatment experience and overall prognosis of these patients.展开更多
Background Surgery plays an important role in the treatment of neuroblastoma.Perioperative complications may impact the course of neuroblastoma treatment.To date,comprehensive analyses of complications and risk factor...Background Surgery plays an important role in the treatment of neuroblastoma.Perioperative complications may impact the course of neuroblastoma treatment.To date,comprehensive analyses of complications and risk factors have been lacking.Methods Patients with retroperitoneal neuroblastoma undergoing tumor resection were retrospectively analyzed between 2014 and 2021.The data collected included clinical characteristics,operative details,operative complications and postopera-tive outcomes.Risk factors for perioperative complications of retroperitoneal neuroblastoma were analyzed.Results A total of 571 patients were enrolled in this study.Perioperative complications were observed in 255(44.7%)patients.Lymphatic leakage(28.4%),diarrhea(13.5%),and injury(vascular,nerve and organ;7.5%)were the most frequent compli-cations.There were three operation-related deaths(0.53%):massive hemorrhage(n=1),biliary tract perforation(n=1)and intestinal necrosis(n=1).The presence of image-defined risk factors(IDRFs)[odds ratio(OR)=2.09,P<0.01],high stage of the International Neuroblastoma Risk Group staging system(INRGSS)(OR=0.454,P=0.04),retroperitoneal lymph node metastasis(OR=2.433,P=0.026),superior mesenteric artery encasement(OR=3.346,P=0.003),and inferior mesenteric artery encasement(OR=2.218,P=0.019)were identified as independent risk factors for perioperative complications.Conclusions Despite the high incidence of perioperative complications,the associated mortality rate was quite low.Perio-perative complications of retroperitoneal neuroblastoma were associated with IDRFs,INRGSS,retroperitoneal lymph node metastasis and vascular encasement.Patients with high-risk factors should receive more serious attention during surgery but should not discourage the determination to pursue total resection of neuroblastoma.展开更多
While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiat...While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical,especially high-risk patients.However,differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy,unclear mechanism,and few drug options.Through compound library screening,we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691.The protein kinase B(AKT)pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation,yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear.Here,we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines.Further evidence including neurites outgrowth,cell cycle arrest,and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691.Meanwhile,with the introduction of other AKT inhibitors,it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation.Furthermore,silencing AKT was found to have the effect of inducing neuroblastoma differentiation.Finally,confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo,suggesting that Hu7691 is a potential molecule against neuroblastoma.Through this study,we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.展开更多
基金supported by the Zhejiang Provincial Nat ural Science Foundation of China(Nos.LZ23C060002 and LZ24H160004)the National Natural Science Foundation of China(Nos.32270746,82203247,82203415,82272637,82204429,and 82073332)+2 种基金the National Key Research and Development Program of China(No.2022YFE0107800)the Medical Interdisciplinary Innovation Program 2024,Zhejiang University School of Medicine,and the Fundamental Research Funds for the Central Universities(No.K20220228)It is add-itionally supported by the National Institute of Health(No.R01-CA200992-03).
文摘Cancer is characterized by abnormal cell proliferation.Cyclins and cyclin-dependent kinases(CDKs)have been recognized as essential regulators of the intricate cell cycle,orchestrating DNA replication and transcription,RNA splicing,and protein synthesis.Dysregulation of the CDK pathway is prevalent in the development and progression of human cancers,rendering cyclins and CDKs attractive therapeutic targets.Several CDK4/6 inhibitors have demonstrated promising anti-cancer efficacy and have been successfully translated into clinical use,fueling the development of CDK-targeted therapies.With this enthusiasm for finding novel CDK-targeting anti-cancer agents,there have also been exciting advances in the field of targeted protein degradation through innovative strategies,such as using proteolysis-targeting chimera,heat shock protein 90(HSP90)-mediated targeting chimera,hydrophobic tag-based protein degradation,and molecular glue.With a focus on the translational potential of cyclin-and CDK-targeting strategies in cancer,this review presents the fundamental roles of cyclins and CDKs in cancer.Furthermore,it summarizes current strategies for the proteasome-dependent targeted degradation of cyclins and CDKs,detailing the underlying mechanisms of action for each approach.A comprehensive overview of the structure and activity of existing CDK degraders is also provided.By examining the structure‒activity relationships,target profiles,and biological effects of reported cyclin/CDK degraders,this review provides a valuable reference for both CDK pathway-targeted biomedical research and cancer therapeutics.
基金funded by the Natural Science Foundation of Zhejiang Province(LZ24H160004 to YC,LZ23C060002 to LX)National Natural Science Foundation of China(82203415 to YC,32270746,82203247 to LX)+1 种基金Medical Interdisciplinary Innovation Program 2024,Zhejiang University School of Medicine(to LX),ZJU-GENSCI Children’s Health Research&Development Center(ZJU-GENSCI2024YY003 to ZPS)the Fundamental Research Funds for the Central Universities(No.K20220228).
文摘Background Pediatric gliomas are the most frequently occurring central nervous system tumors in children.While targeted therapies have been widely applied in the treatment of many adult cancers,their use in pediatric gliomas has lagged behind.However,recent advances in multiomics profiling of pediatric gliomas,coupled with the approval of inhibitors against Raf serine/threonine kinase(RAF),isocitrate dehydrogenase 1/2(IDH1/2)and neurotrophic receptor tyrosine kinase(NTRK),have spurred significant progress in this field.In light of these developments,this review aims to provide a comprehensive overview of current advancements and the evolving landscape of targeted therapeutic strategies and approaches for pediatric gliomas.Data sources Data analyzed in this study were obtained from the literature from PubMed,as well as other online databases and websites,including ClinicalTrials.gov and the Pediatric Neuro-Oncology Consortium.Results Based on findings from multiomics profiling,significant insights have been gained into the genetic and molecular landscape of pediatric gliomas,enabling the identification of key mutations and potentially targetable lesions.These advancements provide rationales for the development of more precise treatment strategies and targeted therapies.Recent approvals of targeted therapies and ongoing clinical trials in pediatric gliomas are converging on the targeting of key signaling molecules and metabolic pathways.Conclusions In the molecular era,targeted therapies offer new hope for more effective and personalized treatment options for pediatric glioma patients.By developing and tailoring treatments to target specific molecular and metabolic vulnerabilities,targeted therapies have the potential to improve the clinical management of pediatric gliomas,ultimately enhancing both the treatment experience and overall prognosis of these patients.
基金supported by General Program of National Natural Science Foundation of China(No.32270853)Key Program of Natural Science Foundation of Zhejiang Province(No.HDMZ23H160029).
文摘Background Surgery plays an important role in the treatment of neuroblastoma.Perioperative complications may impact the course of neuroblastoma treatment.To date,comprehensive analyses of complications and risk factors have been lacking.Methods Patients with retroperitoneal neuroblastoma undergoing tumor resection were retrospectively analyzed between 2014 and 2021.The data collected included clinical characteristics,operative details,operative complications and postopera-tive outcomes.Risk factors for perioperative complications of retroperitoneal neuroblastoma were analyzed.Results A total of 571 patients were enrolled in this study.Perioperative complications were observed in 255(44.7%)patients.Lymphatic leakage(28.4%),diarrhea(13.5%),and injury(vascular,nerve and organ;7.5%)were the most frequent compli-cations.There were three operation-related deaths(0.53%):massive hemorrhage(n=1),biliary tract perforation(n=1)and intestinal necrosis(n=1).The presence of image-defined risk factors(IDRFs)[odds ratio(OR)=2.09,P<0.01],high stage of the International Neuroblastoma Risk Group staging system(INRGSS)(OR=0.454,P=0.04),retroperitoneal lymph node metastasis(OR=2.433,P=0.026),superior mesenteric artery encasement(OR=3.346,P=0.003),and inferior mesenteric artery encasement(OR=2.218,P=0.019)were identified as independent risk factors for perioperative complications.Conclusions Despite the high incidence of perioperative complications,the associated mortality rate was quite low.Perio-perative complications of retroperitoneal neuroblastoma were associated with IDRFs,INRGSS,retroperitoneal lymph node metastasis and vascular encasement.Patients with high-risk factors should receive more serious attention during surgery but should not discourage the determination to pursue total resection of neuroblastoma.
基金supported by the National Natural Science Foundation of China(No.U20A20137)the Zhejiang Provincial Natural Science Foundation of China(No.LD21H310001)the Fundamental Research Funds for the Central Universities(No.2021XZZX037,China)。
文摘While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical,especially high-risk patients.However,differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy,unclear mechanism,and few drug options.Through compound library screening,we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691.The protein kinase B(AKT)pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation,yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear.Here,we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines.Further evidence including neurites outgrowth,cell cycle arrest,and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691.Meanwhile,with the introduction of other AKT inhibitors,it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation.Furthermore,silencing AKT was found to have the effect of inducing neuroblastoma differentiation.Finally,confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo,suggesting that Hu7691 is a potential molecule against neuroblastoma.Through this study,we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.
