Learning from the failures of drug discovery in B-cell non-Hodgkin lymphomas and perspectives for the future: chronic lymphocytic leukemia and diffuse large B-cell lymphoma as two ends of a spectrum in drug development
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Learning from the failures of drug discovery in B-cell non-Hodgkin lymphomas and perspectives for the future: chronic lymphocytic leukemia and diffuse large B-cell lymphoma as two ends of a spectrum in drug development. / Kubuschok, Boris; Trepel, Martin.
in: EXPERT OPIN DRUG DIS, Jahrgang 12, Nr. 7, 07.2017, S. 733-745.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Review › Forschung
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T1 - Learning from the failures of drug discovery in B-cell non-Hodgkin lymphomas and perspectives for the future: chronic lymphocytic leukemia and diffuse large B-cell lymphoma as two ends of a spectrum in drug development
AU - Kubuschok, Boris
AU - Trepel, Martin
PY - 2017/7
Y1 - 2017/7
N2 - INTRODUCTION: Despite substantial recent advances, there is still an unmet need for better therapies in B-cell non Hodgkin lymphomas (B-NHL), especially in relapsed or refractory disease. Many novel targeted drugs have been developed based on a better molecular understanding of B-NHL. Areas covered: This article focuses on chronic lymphocytic leukemia (CLL) as a representative for indolent lymphomas and paradigmatic for the tremendous progress in treating B-NHL on the one hand and diffuse large B-cell lymphoma (DLBCL) as a representative for aggressive lymphomas and paradigmatic for many unsolved problems in lymphoma treatment or the other hand. We highlight salient points in current therapies targeting genetic, epigenetic, immunological and microenvironmental alterations. Possible reasons for drug failure in clinical trials like tumor heterogeneity, clonal evolution and drug resistance mechanisms are discussed. Based thereon, some perspectives for further drug discovery are given. Expert opinion: In view of the pathogenetic complexity of lymphomas, therapies targeting exclusively a single alteration may fail because resistance mechanisms are present either initially or evolve during treatment. Therefore, future therapies in B-NHL may have to target the greatest possible number of genetic, immunological or epigenetic alterations still allowing tolerability and to monitor these alterations during therapy.
AB - INTRODUCTION: Despite substantial recent advances, there is still an unmet need for better therapies in B-cell non Hodgkin lymphomas (B-NHL), especially in relapsed or refractory disease. Many novel targeted drugs have been developed based on a better molecular understanding of B-NHL. Areas covered: This article focuses on chronic lymphocytic leukemia (CLL) as a representative for indolent lymphomas and paradigmatic for the tremendous progress in treating B-NHL on the one hand and diffuse large B-cell lymphoma (DLBCL) as a representative for aggressive lymphomas and paradigmatic for many unsolved problems in lymphoma treatment or the other hand. We highlight salient points in current therapies targeting genetic, epigenetic, immunological and microenvironmental alterations. Possible reasons for drug failure in clinical trials like tumor heterogeneity, clonal evolution and drug resistance mechanisms are discussed. Based thereon, some perspectives for further drug discovery are given. Expert opinion: In view of the pathogenetic complexity of lymphomas, therapies targeting exclusively a single alteration may fail because resistance mechanisms are present either initially or evolve during treatment. Therefore, future therapies in B-NHL may have to target the greatest possible number of genetic, immunological or epigenetic alterations still allowing tolerability and to monitor these alterations during therapy.
KW - Animals
KW - Antineoplastic Agents
KW - Drug Design
KW - Drug Discovery
KW - Drug Resistance, Neoplasm
KW - Epigenesis, Genetic
KW - Humans
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Lymphoma, B-Cell
KW - Lymphoma, Large B-Cell, Diffuse
KW - Molecular Targeted Therapy
KW - Journal Article
KW - Review
U2 - 10.1080/17460441.2017.1329293
DO - 10.1080/17460441.2017.1329293
M3 - SCORING: Review article
C2 - 28494631
VL - 12
SP - 733
EP - 745
JO - EXPERT OPIN DRUG DIS
JF - EXPERT OPIN DRUG DIS
SN - 1746-0441
IS - 7
ER -