title: Developing novel strategies to target B-cell malignancies.
abstract: In the past several years we have seen the identification and validation of several key pathways that drive malignant B-cell development. In addition, the effect nonmalignant effector cells within the immune microenvironment have on tumor survival, proliferation, and possibly chemotherapy resistance is increasingly understood. Although there is still much to be learned, this improved understanding combined with rapid advances in medicinal chemistry focusing on structure-based drug design have resulted in a shift in the development of new agents away from traditional chemotherapy to more selective agents targeting key cellular pathways. Examples of "hot" new therapeutic targets include the B-cell receptor signaling pathway, PI3K/mTOR/AKT pathway, histone deacetylases (HDAC), regulators of apoptosis such as the BCL-2 family, the proteasome, and cell-cell interactions within the tumor environment. Many drugs that target specific agents in early clinical development have demonstrated activity in various subtypes of lymphoma and leukemia. Monoclonal and conjugated antibodies targeting cell surface proteins such as CD19, CD22, CD37, and different epitopes of CD20 have also shown promise in relapsed B-cell malignancies and are rapidly moving into efficacy studies. This review will focus on a few of the new nonantibody-based targeted agents in development, their respective pathways, and their activity in various B-cell malignancies.
authors.affiliation: From the Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Nathan
authors.initials: N
authors.lastname: Fowler
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Oki
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000145:classification / Q000494:pharmacology / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D058990:Molecular Targeted Therapy / Q000639:trends; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061988:Proteasome Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D035703:Therapies, Investigational / Q000379:methods; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011947:Receptors, Antigen, B-Cell; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases