Mechanism of Action Magnifier – 2016 Desk Reference

Welcome to the inaugural edition of our annual Mechanism of Action Magnifier™! The Magnifier series is an exclusive supplement brought to you by the publishers of Personalized Medicine in Oncology (PMO) to delve into the biochemical interaction through which an oncology drug produces its pharmacological effect.

Magnifying Mechanisms of Action: an Exclusive Series to PMO

Dear Colleague,Welcome to the inaugural edition of our annual Mechanism of Action Magnifier™! The Magnifier series is an exclusive supplement brought to you by the publishers of Personalized Medicine in Oncology (PMO) to delve into the biochemical interaction through which an oncology drug produces its pharmacological effect. Throughout the year, [ Read More ]

Dabrafenib plus Trametinib: Two Kinase Inhibitors Used in Combination to Target Different Parts of the MAPK Pathway

The MAPK pathway is constitutively activated in the majority of melanomas as a result of molecular alterations in genes encoding key components of the pathway (eg, BRAF and NRAS mutations) or upstream cell surface receptors (eg, KIT), resulting in uncontrolled tumor proliferation and survival (Figure 1).1 Among patients with metastatic [ Read More ]

Blinatumomab: a Bispecific CD19-Directed CD3 T-Cell Engager

Blinatumomab (derived from “B-lineage–specific antitumor mouse monoclonal antibody”) is a bispecific CD19-directed CD3 T-cell engaging antibody that binds to1-3:CD19 (expressed on the surface of cells of B-lineage origin)CD3 (expressed on the surface of T cells).More than 90% of cases of B-cell precursor acute lymphoblastic leukemia (ALL) express CD19 in more [ Read More ]

Duvelisib (IPI-145): a Dual Inhibitor of Phosphoinositide 3-Kinase (PI3K)-Delta and -Gamma

In B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma, the malignant B cells rely on a number of internal and external stimuli to survive, such as the activation of the B-cell receptor, cytokine and chemokine signaling, or direct cell-to-cell interactions. Attracted by chemo­kines, including CXCL12 and [ Read More ]

Ibrutinib: an Inhibitor of Bruton’s Tyrosine Kinase

B cells circulate between multiple sites in the body during their normal life cycle, and these B cells rely on cues from the support of microenvironments to promote proper development, maturation, and function.1 Chemotaxis to, and adhesion within, proliferative microenvironments, as well as intracellular prosurvival signaling that promotes growth and [ Read More ]

Idelalisib: a Selective Inhibitor of the Delta Isoform of Phosphatidylinositol 3-Kinase

There are 4 isoforms of phosphatidylinositol 3-kinase (PI3K) with distinct functions and expression patterns; among those 4 isoforms, PI3K-alpha and PI3K-beta are ubiquitously expressed and involved in a range of cellular functions.1 Both PI3K-gamma and PI3K-delta are expressed predominantly in normal and malignant hematopoietic cells within the bone marrow.1 PI3K-Delta [ Read More ]

Panobinostat: a Histone Deacetylase Inhibitor

In the cell nucleus, DNA is maintained in a tightly coiled state around proteins called histones.1 During the process of DNA replication for cell division or during the synthesis of RNA and proteins, histone ace­tyltransferase adds acetyl groups onto the histones, enabling DNA to uncoil.1 By contrast, histone deacetylases (HDACs) [ Read More ]

Ruxolitinib: a Kinase Inhibitor That Inhibits Overactive JAK Pathway Signaling

Overactive JAK pathway signaling is a key mechanism of disease in the myeloproliferative neoplasms (MPNs) polycythemia vera and myelofibrosis.1,2 Signaling of the JAK pathway plays a key role in normal cell functioning.3-6 Well-regulated JAK signaling is essential for cell production, cell proliferation, and immune function. Intracellular regulators, such as suppressor [ Read More ]

Venetoclax (ABT-199): a Selective Inhibitor of B-Cell Lymphoma-2

Proteins in the B-cell lymphoma-2 (BCL-2) family are key regulators of apoptosis, and the BCL-2 gene is frequently overexpressed in leukemias and lymphomas.1,2 The BH3-only proteins of the BCL-2 family (ie, those having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this [ Read More ]

Abemaciclib (LY2835219): a Dual Inhibitor of CDK4 and CDK6

Cyclin-dependent kinases (CDKs) 4 and 6 are overactive in many human cancers, resulting in a loss of regulation of the G1 cell cycle restriction point and making malignant cells less responsive to normal growth controls.1,2 CDK4 and CDK6 CDKs are key regulators of cell proliferation.3 In many tumor types, CDK4 [ Read More ]

Lenvatinib: a Receptor Tyrosine Kinase Inhibitor

Lenvatinib (Figure) is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors1:VEGFR1 (FLT1)VEGFR2 (KDR)VEGFR3 (FLT4).Lenvatinib also inhibits other RTKs involved in tumor proliferation, including1:Fibroblast growth factor receptors 1, 2, 3, and 4The [ Read More ]

Alectinib: an Anaplastic Lymphoma Kinase (ALK) Inhibitor

ALK Rearrangements in Lung AdenocarcinomaALK has been found to fuse with other partners, leading to potent malignant transformation.1,2 The most common among ALK fusion genes in lung cancer, specifically non–small cell lung cancer (NSCLC), is the EML4 ALK translocation fusion gene (EML4-ALK).1,3-5 The relative prevalence of ALK translocation mutations among [ Read More ]

Bavituximab: a Novel, Investigational Immunotherapy Agent Targeting Phosphatidylserine in the Vasculature of the Tumor Microenvironment

Bavituximab is a first-in-class phosphatidylserine (PS)-targeting monoclonal antibody that blocks PS-mediated immunosuppression by multifocal reprogramming of immune cells in the tumor microenvironment to support immune activation.1 PS is a highly immunosuppressive molecule usually located inside the membrane of healthy cells, but “flips” and becomes exposed on the outside of cells [ Read More ]

Necitumumab: an Epidermal Growth Factor Receptor Antibody

Overexpression of the epidermal growth factor receptor (EGFR) is correlated with poor prognosis in many human cancers.1 EGFR is a member of the ErbB family of receptor tyrosine kinases (TKs). EGFR activation occurs in response to ligand stimulation and/or genetic alterations of the EGFR gene, such as somatic mutations, amplifications, [ Read More ]

Trabectedin: a DNA-Binding Agent That Covalently Interacts with the Minor Groove of the DNA Double Helix

Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by 3 fused tetrahydroisoquinoline rings.1 Trabectedin binds to the minor groove of DNA and alkylates guanine at the N2 position, bending the helix toward the major groove.2,3 In this manner, it is [ Read More ]