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

TY - JOUR

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 -