Recombinant tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal–regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their micro-environment to enhance the concentrations of the endogenous tumor suppressor TRAIL.

• Selective myeloma cell killing and enhanced effector function of a novel anti-BCMA antibody conjugated with MMAF via noncleavable linker.• Specific multiple myeloma antigen for monoclonal antibody-based immunotherapy.B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G 2 /M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared with the wild-type J6M0 without Fc enhancement. The antibody-dependent cell-mediated cytotoxicity and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer. (Blood. 2014;123(20):3128-3138) IntroductionAlthough there is no monoclonal antibody (mAb)-based targeted therapy approved to treat patients with multiple myeloma (MM), many mAbs targeting different antigens have been preclinically and clinically evaluated. ) were either moved toward or remain in clinical development based on encouraging results from preclinical studies. However, these antigens still lack specificity and are also expressed in other normal tissues including natural killer (NK) or other effectors, which could limit their clinical utility. Therefore, novel therapeutic mAbs to achieve improved MM selectivity, simultaneously targeting cytotoxic drugs to MM cells, are urgently needed.B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily (TNFRSF17), is selectively induced during plasma cell differentiation and is nearly absent on naive and memory B cells. 13,14 Upon binding to its ligands B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), the survival of bone marrow (BM) plasma cells and plasmablasts is promoted.15,16 BCMA does not maintain normal B-cell homeostasis, but is required for the survival of long-lived plasma cells. 17 In MM, BCMA messenger RNA (mRNA) is commonly expressed at high levels in malignant plasma...

Purpose: To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo.Experimental Design: Immune effects of dabrafenib and trametinib were evaluated in human CD4 þ and CD8 þ T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model.

SUMMARY Oncogenic Myc alters mitochondrial metabolism, making it dependent on exogenous glutamine (Gln) for cell survival. Accordingly, Gln deprivation selectively induces apoptosis in MYC-overexpressing cells via unknown mechanisms. Using MYCN-amplified neuroblastoma as a model, we identify PUMA, NOXA and TRB3 as executors of Gln-starved cells. Gln depletion in MYC-transformed cells induces apoptosis through ATF4-dependent, but p53-independent, PUMA and NOXA induction. MYC-transformed cells depend on both glutamate-oxaloacetate transaminase and glutamate dehydrogenase to maintain Gln homeostasis and suppress apoptosis. Consequently, either ATF4 agonists or glutaminolysis inhibitors potently induce apoptosis in vitro and inhibit tumor growth in vivo. These results reveal mechanisms whereby Myc sensitizes cells to apoptosis and validate ATF4 agonists and inhibitors of Gln metabolism as potential Myc-selective cancer therapeutics.