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Signal Transduction and Targeted Therapy 2019年第1期4卷 240-242页

作者： Tingting wang Margaret Shatara Fangbing Liu Tristan Knight Holly Edwards Guan wang Hai Lin Yue wang jeffrey w.taub Yubin Ge National Engineering Laboratory for AIDS Vaccine Key Laboratory for Molecular Enzymology and Engineeringthe Ministry of EducationSchool of Life SciencesJilin University130021 ChangchunPeople’s Republic of China Division of Pediatric Hematology/Oncology Department of PediatricsChildren’s Hospital of MichiganDetroitMI 48201USA Department of Pediatrics Wayne State University School of MedicineDetroitMI 48201USA Department of Oncology Wayne State University School of MedicineDetroitMI 48201USA Molecular Therapeutics Program Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitMI 48201USA Department of Hematology and Oncology The First Hospital of Jilin University130021 ChangchunPeople’s Republic of China Department of Pediatric Hematology and Oncology The First Hospital of Jilin University130021 ChangchunPeople’s Republic of China

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 *** Pol I transcription rate is higher in AML cells than nonleukemic myeloid precursors 2,suggesting Pol I transcrip-tion as a therapeutic target for ***-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.

关键词： myeloid acute leukemic

Targeting multiple signaling pathways:the new approach to acute myeloid leukemia therapy

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Signal Transduction and Targeted Therapy 2021年第1期6卷 41-69页

作者： Jenna LCarter Katie Hege Jay Yang Hasini AKalpage Yongwei Su Holly Edwards Maik Hüttemann jeffrey wtaub Yubin Ge Cancer Biology Graduate Program Wayne State University School of MedicineDetroitMIUSA MD/PhD Program Wayne State University School of MedicineDetroitMIUSA Department of Oncology Wayne State University School of MedicineDetroitMIUSA Molecular Therapeutics Program Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitMIUSA Center for Molecular Medicine and Genetics Wayne State University School of MedicineDetroitMIUSA National Engineering Laboratory for AIDS Vaccine Key Laboratory for Molecular Enzymology and EngineeringThe Ministry of EducationSchool of Life SciencesJilin UniversityChangchunChina Division of Pediatric Hematology/Oncology Children’s Hospital of MichiganDetroitMIUSA Department of Pediatrics Wayne State University School of MedicineDetroitMIUSA

Acute myeloid leukemia(AML)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in *** this,very little improvement in survival rates has been achieved over the past few *** 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 *** the past 20 years,research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and *** 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 *** 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 *** 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 *** 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 *** 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.

关键词： myeloid approach approval

Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells

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Signal Transduction and Targeted Therapy 2017年第1期2卷 242-250页

作者： Daniel A Luedtke Xiaojia Niu Yihang Pan Jianyun Zhao Shuang Liu Holly Edwards Kang Chen Hai Lin jeffrey w taub Yubin Ge Cancer Biology Graduate Program Wayne State University School of MedicineDetroitMichiganUSA National Engineering Laboratory for AIDS Vaccine School of Life SciencesJilin UniversityChangchunChina Department of Pathology and Laboratory Medicine Weill Cornell MedicineNew YorkNew YorkUSA Department of Pediatrics Wayne State University School of MedicineDetroitMichiganUSA Department of Oncology Wayne State University School of MedicineDetroitMichiganUSA Molecular Therapeutics Program Karmanos Cancer InstituteWayne State University School of MedicineDetroitMichiganUSA Department of Obstetrics and Gynecology Wayne State University School of MedicineDetroitMichiganUSA Mucosal Immunology Studies Team National Institute of Allergy and Infectious DiseasesNational Institutes of HealthBethesdaMarylandUSA Department of Hematology and Oncology The First Hospital of Jilin UniversityChangchunChina Division of Pediatric Hematology and Oncology Children’s Hospital of MichiganDetroitMichiganUSA.

Acute myeloid leukemia(AML)is a serious *** 5-year survival rates remain frustratingly low(65%for children and 26%for adults).Resistance to frontline chemotherapy(usually cytarabine)often develops;therefore a new treatment modality is ***-2 family proteins play an important role in balancing cell survival and *** antiapoptotic Bcl-2 family proteins have been found to be dysregulated in ***-199,a BH3 mimetic,was developed to target antiapoptotic protein *** ABT-199 has demonstrated promising results,resistance *** studies in AML show that ABT-199 alone decreases the association of proapoptotic protein Bim with Bcl-2,but this is compensated by increased association of Bim with prosurvival protein Mcl-1,stabilizing Mcl-1,resulting in resistance to *** this study,we investigated the antileukemic activity of the Mcl-1-selective inhibitor A-1210477 in combination with ABT-199 in AML *** found that A-1210477 synergistically induced apoptosis with ABT-199 in AML cell lines and primary patient *** synergistic induction of apoptosis was decreased upon Bak,Bax and Bim *** A-1210477 treatment alone also increased Mcl-1 protein levels,combination with ABT-199 reduced binding of Bim to *** results demonstrate that sequestration of Bim by Mcl-1,a mechanism of ABT-199 resistance,can be abrogated by combined treatment with the Mcl-1 inhibitor A-1201477.

关键词： chemotherapy alone treatment

Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia

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Signal Transduction and Targeted Therapy 2020年第1期5卷 2332-2342页

作者： Daniel A.Luedtke Yongwei Su Jun Ma Xinyu Li Steven ABuck Holly Edwards Lisa Polin Juiwanna Kushner Sijana HDzinic Kathryn white Hai Lin jeffrey wtaub Yubin Ge Cancer Biology Graduate Program Wayne State University School of MedicineDetroitMI 48201USA School of Life Sciences Jilin University130021 ChangchunChina Division of Pediatric Hematology and Oncology Children’s Hospital of MichiganDetroitMIUSA48201 Department of Pediatrics Wayne State University School of MedicineDetroitMI 48201USA Department of Oncology Wayne State University School of MedicineDetroitMI 48201USA Molecular Therapeutics Program Karmanos Cancer InstituteWayne State University School of MedicineDetroitMI 48201USA Department of Hematology and Oncology The First Hospital of Jilin University130021 ChangchunChina

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 *** 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 ***9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and ***,downregulation of Mcl-1 is transient,which necessitates an intermittent treatment schedule to allow for repeated downregulation of ***,an every other day schedule of the CDK9 inhibitor is effective in vitro and in vivo in enhancing the efficacy of *** preclinical data provide a rationale for an intermittent drug administration schedule for the clinical evaluation of the combination treatment for AML.

关键词： venetoclax clinical CDK9