Genetic and Molecular Targets in Lymphoma
Genetic and Molecular Targets in Lymphoma
Lymphomas are the most common hematologic malignancies with approximately 79,000 new cases estimated for 2013 in the USA. Despite improved outcomes, relapse or recurrence remains a common problem with conventional cytotoxic therapy. Recently, many genetic and molecular mechanisms that drive various cellular events like apoptosis, angiogenesis and cell motility have been more clearly delineated. These new findings, coupled with the advent of high-throughput screening technology have led to the discovery of many compounds that can target specific mutations and/or influence deregulated transcription. In this review, we intend to provide a concise overview of genetic and molecular events that drive cellular processes in lymphomas and represent potential therapeutic targets. Additionally, we briefly discuss the prognostic significance of select biological markers.
Lymphomas can present with a wide spectrum of clinical manifestation and are a heterogeneous group of multiple subtypes, which can be subdivided into Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL). Approximately 85% of all lymphomas are of B-cell origin, while the remainder are derived from T or NK cells. The burden of this disease is high with approximately 79,000 new cases and 20,000 deaths expected in the United States for 2013. Except for a few indolent lymphomas that are managed with close observation, most clinically manifested lymphomas require treatment with radiation, chemotherapy or immunotherapy (monoclonal antibodies) each treatment modality in combination or alone. Despite a high rate of initial remissions, eventually many patients with NHL experience a relapse. The management of relapse often poses a clinical challenge. Hematopoietic stem cell transplantation can improve overall survival (OS) and event-free survival (EFS) when compared with second-line chemotherapy alone for relapsed NHL. But not all patients are eligible for hematopoietic stem cell transplantation and curative treatment options for these patients are limited. Thus looking beyond the current available options, by in-depth analysis of the pathobiology of lymphomas, will help advance care.
Better understanding of how established etiologic factors influence lymphomagenesis suggests complex interplay of aberrant cell-cycle regulation, deregulated cytokines, loss of normal immune-surveillance and epigenetic abnormalities. Different oncogenic mechanisms may apply to different subtypes within one subcategory and highlight the molecular heterogeneity within individual lymphomas. This is exemplified by gene-expression studies performed in diffuse large B-cell lymphoma (DLBCL), where germinal center B-cell (GCB) and activated B-cell (ABC) variants are driven by distinctly different mechanisms with variable prognosis. Such complex heterogeneity showcases the need to develop more targeted strategies. In this review, we will focus on describing genetic and molecular targets in lymphomas that have potential therapeutic implications. In addition to the prognostic significance of these targets, we will briefly summarize the novel agents furthest along in clinical development. The confines of this review make it impossible to adequately cover antibodies targeting the lymphoma surface and readers are therefore advised to refer to an excellent overview provided by Fanale et al.
Abstract and Introduction
Abstract
Lymphomas are the most common hematologic malignancies with approximately 79,000 new cases estimated for 2013 in the USA. Despite improved outcomes, relapse or recurrence remains a common problem with conventional cytotoxic therapy. Recently, many genetic and molecular mechanisms that drive various cellular events like apoptosis, angiogenesis and cell motility have been more clearly delineated. These new findings, coupled with the advent of high-throughput screening technology have led to the discovery of many compounds that can target specific mutations and/or influence deregulated transcription. In this review, we intend to provide a concise overview of genetic and molecular events that drive cellular processes in lymphomas and represent potential therapeutic targets. Additionally, we briefly discuss the prognostic significance of select biological markers.
Introduction
Lymphomas can present with a wide spectrum of clinical manifestation and are a heterogeneous group of multiple subtypes, which can be subdivided into Hodgkin's (HL) and non-Hodgkin's lymphoma (NHL). Approximately 85% of all lymphomas are of B-cell origin, while the remainder are derived from T or NK cells. The burden of this disease is high with approximately 79,000 new cases and 20,000 deaths expected in the United States for 2013. Except for a few indolent lymphomas that are managed with close observation, most clinically manifested lymphomas require treatment with radiation, chemotherapy or immunotherapy (monoclonal antibodies) each treatment modality in combination or alone. Despite a high rate of initial remissions, eventually many patients with NHL experience a relapse. The management of relapse often poses a clinical challenge. Hematopoietic stem cell transplantation can improve overall survival (OS) and event-free survival (EFS) when compared with second-line chemotherapy alone for relapsed NHL. But not all patients are eligible for hematopoietic stem cell transplantation and curative treatment options for these patients are limited. Thus looking beyond the current available options, by in-depth analysis of the pathobiology of lymphomas, will help advance care.
Better understanding of how established etiologic factors influence lymphomagenesis suggests complex interplay of aberrant cell-cycle regulation, deregulated cytokines, loss of normal immune-surveillance and epigenetic abnormalities. Different oncogenic mechanisms may apply to different subtypes within one subcategory and highlight the molecular heterogeneity within individual lymphomas. This is exemplified by gene-expression studies performed in diffuse large B-cell lymphoma (DLBCL), where germinal center B-cell (GCB) and activated B-cell (ABC) variants are driven by distinctly different mechanisms with variable prognosis. Such complex heterogeneity showcases the need to develop more targeted strategies. In this review, we will focus on describing genetic and molecular targets in lymphomas that have potential therapeutic implications. In addition to the prognostic significance of these targets, we will briefly summarize the novel agents furthest along in clinical development. The confines of this review make it impossible to adequately cover antibodies targeting the lymphoma surface and readers are therefore advised to refer to an excellent overview provided by Fanale et al.