Acute myeloid leukemia(AML)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children.Despite this,very little improvement in survival rates has been achieved ove...Acute myeloid leukemia(AML)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children.Despite this,very little improvement in survival rates has been achieved over the past few decades.This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years.In the past 20 years,research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival.Here we review the development of novel therapeutics in targeting apoptosis,receptor tyrosine kinase(RTK)signaling,hedgehog(HH)pathway,mitochondrial function,DNA repair,and c-Myc signaling.There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells.In addition,we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways.We also describe the complexity of targeting leukemia stem cells(LSCs)as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival.This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.展开更多
Venetoclax,an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia(AML),is tolerated well in elderly patients with AML and has good overall response rates...Venetoclax,an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia(AML),is tolerated well in elderly patients with AML and has good overall response rates;however,resistance remains a concern.In this study,we show that targeting CDK9 with voruciclib in combination with venetoclax results in synergistic antileukemic activity against AML cell lines and primary patient samples.CDK9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and c-Myc.However,downregulation of Mcl-1 is transient,which necessitates an intermittent treatment schedule to allow for repeated downregulation of Mcl-1.Accordingly,an every other day schedule of the CDK9 inhibitor is effective in vitro and in vivo in enhancing the efficacy of venetoclax.Our preclinical data provide a rationale for an intermittent drug administration schedule for the clinical evaluation of the combination treatment for AML.展开更多
Dear Editor,Continued development of novel therapeutic agents is critical to improve the survival of patients with acute myeloid leukemia(AML).RNA Polymerase I(Pol I)-mediated transcription and ribosomal biogenesis be...Dear Editor,Continued development of novel therapeutic agents is critical to improve the survival of patients with acute myeloid leukemia(AML).RNA Polymerase I(Pol I)-mediated transcription and ribosomal biogenesis become dysregulated,thereby allowing synthesis of necessary substrates to support uncontrolled cancer cell proliferation 1.The Pol I transcription rate is higher in AML cells than nonleukemic myeloid precursors 2,suggesting Pol I transcrip-tion as a therapeutic target for AML.CX-5461 is a potent Pol I transcription inhibitor and stabilizer of the DNA G-quadruplex structure,which causes G2/M-phase arrest via the ATR(ataxia telangiectasia and Rad3-related protein)-mediated DNA damage response(DDR)3–5.展开更多
Acute myeloid leukemia(AML)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children.Despite this,very little improvement in survival rates has been achieved ove...Acute myeloid leukemia(AML)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children.Despite this,very little improvement in survival rates has been achieved over the past few decades.This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years.In the past 20 years,research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival.Here we review the development of novel therapeutics in targeting apoptosis,receptor tyrosine kinase(RTK)signaling,hedgehog(HH)pathway,mitochondrial function,DNA repair,and c-Myc signaling.There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells.In addition,we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways.We also describe the complexity of targeting leukemia stem cells(LSCs)as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival.This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.展开更多
文摘Acute myeloid leukemia(AML)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children.Despite this,very little improvement in survival rates has been achieved over the past few decades.This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years.In the past 20 years,research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival.Here we review the development of novel therapeutics in targeting apoptosis,receptor tyrosine kinase(RTK)signaling,hedgehog(HH)pathway,mitochondrial function,DNA repair,and c-Myc signaling.There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells.In addition,we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways.We also describe the complexity of targeting leukemia stem cells(LSCs)as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival.This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.
文摘Venetoclax,an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia(AML),is tolerated well in elderly patients with AML and has good overall response rates;however,resistance remains a concern.In this study,we show that targeting CDK9 with voruciclib in combination with venetoclax results in synergistic antileukemic activity against AML cell lines and primary patient samples.CDK9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and c-Myc.However,downregulation of Mcl-1 is transient,which necessitates an intermittent treatment schedule to allow for repeated downregulation of Mcl-1.Accordingly,an every other day schedule of the CDK9 inhibitor is effective in vitro and in vivo in enhancing the efficacy of venetoclax.Our preclinical data provide a rationale for an intermittent drug administration schedule for the clinical evaluation of the combination treatment for AML.
基金This study was supported by Jilin University,Changchun,Chinathe Barbara Ann Karmanos Cancer Institute+2 种基金Wayne State University School of Medicinegrants from the National Natural Science Foundation of China(NSFC 31671438 and NSFC 31471295)National Key Research and Development Program of China(2017YFC1702103)。
文摘Dear Editor,Continued development of novel therapeutic agents is critical to improve the survival of patients with acute myeloid leukemia(AML).RNA Polymerase I(Pol I)-mediated transcription and ribosomal biogenesis become dysregulated,thereby allowing synthesis of necessary substrates to support uncontrolled cancer cell proliferation 1.The Pol I transcription rate is higher in AML cells than nonleukemic myeloid precursors 2,suggesting Pol I transcrip-tion as a therapeutic target for AML.CX-5461 is a potent Pol I transcription inhibitor and stabilizer of the DNA G-quadruplex structure,which causes G2/M-phase arrest via the ATR(ataxia telangiectasia and Rad3-related protein)-mediated DNA damage response(DDR)3–5.
文摘Acute myeloid leukemia(AML)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in children.Despite this,very little improvement in survival rates has been achieved over the past few decades.This is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 years.In the past 20 years,research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and survival.Here we review the development of novel therapeutics in targeting apoptosis,receptor tyrosine kinase(RTK)signaling,hedgehog(HH)pathway,mitochondrial function,DNA repair,and c-Myc signaling.There has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML cells.In addition,we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival pathways.We also describe the complexity of targeting leukemia stem cells(LSCs)as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC survival.This comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.
