Current cancer therapies have encountered adverse response due to poor therapeutic efficiency,severe side effects and acquired resistance to multiple drugs.Thus,there are urgent needs for finding new cancer-targeted p...Current cancer therapies have encountered adverse response due to poor therapeutic efficiency,severe side effects and acquired resistance to multiple drugs.Thus,there are urgent needs for finding new cancer-targeted pharmacological strategies.In this review,we summarized the current understanding with THZ1,a covalent inhibitor of cyclin-dependent kinase 7(CDK7),which demonstrated promising anti-tumor activity against different cancer types.By introducing the anti-tumor behaviors and the potential targets for different cancers,this review aims to provide more effective approaches to CDK7 inhibitor-based therapeutic agents and deeper insight into the diverse tumor proliferation mechanisms.展开更多
Traditional therapies such as surgery and endocrine therapy no longer meet the clinical needs in prostate cancer treatment,and more effective treatments are urgently required.Recent studies have reported that targeted...Traditional therapies such as surgery and endocrine therapy no longer meet the clinical needs in prostate cancer treatment,and more effective treatments are urgently required.Recent studies have reported that targeted inhibition of the transcription factor cyclin dependent kinase 7(CDK7)could effectively suppress prostate cancer progression.However,the toxicity of CDK7 inhibitors such as THZ1 is the main limitation of the clinical application.In this work,we synthesized Cys8E(C8E)nanoparticles(NPs)loaded with THZ1(C8E@THZ1),a novel GSH-targeting and stimuli-responsive nano-delivery platform,and investigated its anti-tumor potential and biosafety properties.In vitro,C8E@THZ1 potently inhibited the proliferation and promoted the apoptosis of prostate cancer cells.On tumor-bearing mice,C8E@THZ1 inhibited tumors by up to 85%,while the damage of THZ1 to liver function was effectively avoided.These results confirmed that inhibition of CDK7 can effectively block the progression of prostate cancer,and that Cys8E NPs is a highly prospective delivery platform to promote the clinical application of CDK7 inhibitors.展开更多
Background:Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer(TNBC).One of the immunosuppressive pathways involves programmed cell death-1(PD-1)and programmed cell death lig...Background:Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer(TNBC).One of the immunosuppressive pathways involves programmed cell death-1(PD-1)and programmed cell death ligand-1(PD-L1),but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment.Prior research has shown that MYC,a master transcription amplifier highly expressed in TNBC cells,can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy.This study aims to investigate the regulatory relationship between MYC and PD-L1,and whether a cyclin-dependent kinase(CDK)inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy.Methods:Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1.The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting.A patient-derived tumor xenograft(PDTX)model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression.Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine(EdU)cell proliferation and cell migration assays.Tumor xenograft models were established for in vivo verification.Results:A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells(TIICs).The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients.Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein.In addition,antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1.Conclusions:The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect,which might offer new insight for enhancing immunotherapy in TNBC.展开更多
文摘Current cancer therapies have encountered adverse response due to poor therapeutic efficiency,severe side effects and acquired resistance to multiple drugs.Thus,there are urgent needs for finding new cancer-targeted pharmacological strategies.In this review,we summarized the current understanding with THZ1,a covalent inhibitor of cyclin-dependent kinase 7(CDK7),which demonstrated promising anti-tumor activity against different cancer types.By introducing the anti-tumor behaviors and the potential targets for different cancers,this review aims to provide more effective approaches to CDK7 inhibitor-based therapeutic agents and deeper insight into the diverse tumor proliferation mechanisms.
基金supported by the National Key R&D Plan of China(No.2022YFC3602904)the National Natural Science Foundation of China(Nos.81974395,82173036)+11 种基金Guangdong Basic and Applied Basic Research Foundation(No.2019A1515011437)International Science and Technology Cooperation Project Plan of Guangdong Province(No.2021A0505030085)Sun Yat-Sen University Clinical Research 5010 Program(No.2019005)Beijing Bethune Charitable Foundation(No.mnzl202001)Guangzhou Science and Technology Key R&D Project(No.202206010117)Beijing CSCO Clinical Oncology Research Foundation(Nos.Ytongshu2021/ms-0162,Y-MSDZD2022-0760)Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation(No.2020B1212060018OF006)Guangdong Provincial Clinical Research Center for Urological Diseases(No.2020B1111170006)supported by the National Natural Science Foundation of China(Nos.52173150,51973243)supported by the National Natural Science Foundation of China(No.82173088)Natural Science Foundation of Guangdong(No.2022A1515012383)the Guangzhou Science and Technology Fund(No.A202201011299)
文摘Traditional therapies such as surgery and endocrine therapy no longer meet the clinical needs in prostate cancer treatment,and more effective treatments are urgently required.Recent studies have reported that targeted inhibition of the transcription factor cyclin dependent kinase 7(CDK7)could effectively suppress prostate cancer progression.However,the toxicity of CDK7 inhibitors such as THZ1 is the main limitation of the clinical application.In this work,we synthesized Cys8E(C8E)nanoparticles(NPs)loaded with THZ1(C8E@THZ1),a novel GSH-targeting and stimuli-responsive nano-delivery platform,and investigated its anti-tumor potential and biosafety properties.In vitro,C8E@THZ1 potently inhibited the proliferation and promoted the apoptosis of prostate cancer cells.On tumor-bearing mice,C8E@THZ1 inhibited tumors by up to 85%,while the damage of THZ1 to liver function was effectively avoided.These results confirmed that inhibition of CDK7 can effectively block the progression of prostate cancer,and that Cys8E NPs is a highly prospective delivery platform to promote the clinical application of CDK7 inhibitors.
基金Key International Cooperation of the National Natural Science Foundation of China(No. 81920108029)Key Foundation for Social Development Project of the Jiangsu Province, China(No. BE2021741)
文摘Background:Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer(TNBC).One of the immunosuppressive pathways involves programmed cell death-1(PD-1)and programmed cell death ligand-1(PD-L1),but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment.Prior research has shown that MYC,a master transcription amplifier highly expressed in TNBC cells,can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy.This study aims to investigate the regulatory relationship between MYC and PD-L1,and whether a cyclin-dependent kinase(CDK)inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy.Methods:Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1.The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting.A patient-derived tumor xenograft(PDTX)model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression.Cell proliferation and migration were detected by 5-ethynyl-2′-deoxyuridine(EdU)cell proliferation and cell migration assays.Tumor xenograft models were established for in vivo verification.Results:A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells(TIICs).The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients.Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein.In addition,antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1.Conclusions:The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect,which might offer new insight for enhancing immunotherapy in TNBC.
