Beyond chemotherapy: new agents for targeted treatment of lymphoma

Abstract

An improved understanding of the molecular biology of cancer cell growth and survival and the role of the microenvironment in supporting the survival of cancer cells, including lymphoma cells, has led to the identification of a number of potential therapeutic targets. Despite these advances, drug development for lymphoma remains slow, inefficient, and frequently unfocused. Future work should focus on identifying 'driver' molecular defects of oncogenic pathways that can be targeted therapeutically, discovering predictive biomarkers for treatment response, and prioritizing promising drugs to accelerate their approval. This Review summarizes the current development status of novel agents for lymphoma and discusses strategies to move the field forward.

Figure 1

Targeted therapy for lymphoma treatment. Cancer cells express a variety of receptors and antigens that can be targeted by monoclonal antibodies. Many of these receptors trigger well-defined signaling pathways that promote the growth and survival of lymphoma cells, including NF-κB, ERK, PI3K/Akt/mTOR JAK/STAT, and extrinsic and/or intrinsic apoptosis pathways. These signaling pathways can be targeted by a variety of small-molecule inhibitors. Abbreviations: ERK, extracellular signal-regulated kinase; JAK/STAT, janus kinase/signal transducer and activator of transcription; NF-κB, nuclear factor-kappa-B; RANK, receptor activator for NF-κB; TRAIL-R1, tumor necrosis factor–related apoptosis-inducing ligand death receptor R1. Reproduced from Hematology by Anas Younes. Copyright 2009 by American Society of Hematology (ASH). Reproduced with permission of American Society of Hematology (ASH) in the format Journal via Copyright Clearance Center.

Figure 2

Targeting the PI3K/Akt/mTOR pathway to treat lymphoma. Pharmacological inhibition of mTORC1 with rapalogs has produced clinical responses in patients with relapsed non-Hodgkin lymphoma and classic Hodgkin lymphoma. Second-generation mTOR inhibitors and inhibitors of upstream molecules such as Akt and PI3K are currently in clinical trials. Frequently, cancer cells have several activated survival pathways, including the MEK/ERK, NF-κB, and JAK/STAT pathways. A combination of small molecules may be required to target these pathways. Abbreviations: ERK, extracellular signal-regulated kinase; JAK, Janus kinase; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappa-B; PI3K, phosphatidylinositol 3-kinase; STAT, signal transducer and activator of transcription; TSC, tuberous sclerosis complex. Reproduced from Hematology by Anas Younes. Copyright 2009 from the American Society of Hematology (ASH). Reproduced with permission of American Society of Hematology (ASH) in the format Journal via Copyright Clearance Center.

Figure 3

Summary of single agents with activity in patients with relapsed diffuse large B-cell lymphoma. This chart is not meant to compare drugs with one another because these data are derived from a variety of phase I and II studies, some of which are ongoing. Single-agent overall response rates of targeted agents rarely exceed 30%. Drugs that are shown in yellow are currently in pivotal trials.