SummaryBET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.

The attrition rate for anticancer drugs entering clinical trials is unacceptably high. For multiple myeloma (MM), we postulate that this is because of preclinical models that overemphasize the antiproliferative activity of drugs, and clinical trials performed in refractory end-stage patients. We validate the Vk*MYC transgenic mouse as a faithful model to predict single-agent drug activity in MM with a positive predictive value of 67% (4 of 6) for clinical activity, and a negative predictive value of 86% (6 of 7) for clinical inactivity. We identify 4 novel agents that should be prioritized for evaluation in clinical trials. Transplantation of Vk*MYC tumor cells into congenic mice selected for a more aggressive disease that models end-stage drug-resistant MM and responds only to combinations of drugs with single-agent activity in untreated Vk*MYC MM. We predict that combinations of standard agents, histone deacetylase inhibitors, bromodomain inhibitors, and hypoxia-activated prodrugs will demonstrate efficacy in the treatment of relapsed MM. (Blood. 2012;120(2):376-385)

Ribosome biogenesis and protein synthesis are dysregulated in many cancers, with those driven by the proto-oncogene c-MYC characterized by elevated Pol I-mediated ribosomal rDNA transcription and mTORC1/eIF4E-driven mRNA translation. Here, we demonstrate that coordinated targeting of rDNA transcription and PI3K-AKT-mTORC1-dependent ribosome biogenesis and protein synthesis provides a remarkable improvement in survival in MYCdriven B lymphoma. Combining an inhibitor of rDNA transcription (CX-5461) with the mTORC1 inhibitor everolimus more than doubled survival of Eμ-Myc lymphoma-bearing mice. The ability of each agent to trigger tumor cell death via independent pathways was central to their synergistic efficacy. CX-5461 induced nucleolar stress and p53 pathway activation, whereas everolimus induced expression of the proapoptotic protein BMF that was independent of p53 and reduced expression of RPL11 and RPL5. Thus, targeting the network controlling the synthesis and function of ribosomes at multiple points provides a potential new strategy to treat MYC-driven malignancies. SIGNIFICANCE:Treatment options for the high proportion of cancers driven by MYC are limited. We demonstrate that combining pharmacologic targeting of ribosome biogenesis and mTORC1-dependent translation provides a remarkable therapeutic benefit to Eμ-Myc lymphoma-bearing mice. These results establish a rationale for targeting ribosome biogenesis and function to treat MYC-driven cancer. Cancer Discov; 6(1);[59][60][61][62][63][64][65][66][67][68][69][70]

Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating ␣-galactosylceramide IntroductionHematologic malignancies typically express the necessary machinery for eliciting antitumor immunity, such as costimulatory molecules, yet many tumors are poorly immunogenic. Therapeutic vaccination strategies that incorporate immune adjuvants are likely to enhance immune recognition and targeting of hematologic cancers, an example being in mice vaccinated against mouse lymphomas with whole tumor cells loaded with CpG adjuvant. 1 Natural killer T (NKT) lymphocytes represent an immune regulatory population with recognized capacity for inducing innate (eg, NK cells) and adaptive (eg, CD8 T cell) antitumor immunity, [2][3][4] by their unique ability to rapidly produce large quantities of cytokines on TCR ligation, in particular IFN-␥. 5,6 As a result, the synthetic CD1d-dependent NKT cell ligand ␣-galactosylceramide (␣-GalCer) has been used for its NKT cell-mediated immune adjuvant properties in anticancer therapies. [7][8][9][10] Initial attempts to stimulate NKT cells in situ were to simply infuse soluble ␣-GalCer, which briefly inhibited the tumor growth, but had limited effects on survival. 11,12 In addition, multiple injections of ␣-GalCer led to deleterious effects including long-term NKT cell functional anergy or unresponsiveness. 12 Subsequently, ␣-GalCer was loaded onto dendritic cells (DCs) as a vaccine. This approach induced more potent antitumor effects than soluble ␣-GalCer injections, mainly by prolonging NKT cell IFN-␥ production and preventing induction of NKT cell anergy, and was able to significantly improve the activity of the DC vaccine if coadministered with tumor antigens. 10,13,14 The cumbersome nature of inducing and expanding DC from patients' peripheral blood monocytes for autologous ␣-GalCerpulsed DC therapy stimulated the use of irradiated tumor cells as a vehicle to deliver ␣-GalCer in vivo. [15][16][17] Here a full complement of tumor antigens (including undefined ones) and ␣-GalCer are codelivered, thus allowing generation of innate immunity and potentially long-term tumor-specific T-cell adaptive immunity. In a prophylactic setting, whole tumor cells loaded with ␣-GalCer were able to protect mice against subsequent challenge with live tumor cells 15,16 and were also shown to be partially effective at inhibiting growth of established solid tumors 17 (S.R.M., K.S., M. Li, H.D., S.F. Ngiow, M.J.S., Transient Foxp3 ϩ regulatory T cell depletion enhances therapeutic anticancer vaccination targeting the immunestimulatory properties of NKT cells, manuscript submitted, August 2012), demonstrating the ability of this vaccine to work successfully in a The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by ...

No abstract

Federation, where some specialists had advocated the DOTS strategy as a "cost-effective" panacea for rising tuberculosis rates 3 -without mention of the need to diagnose and treat already prevalent drug-resistant strains -a manyfold increase in multidrug-resistant tuberculosis has been observed. 4 In Belarus, more than 35% of new tuberculosis cases involve multidrug-resistant strains. 5 These trends are alarming and have undoubtedly been exacerbated by a serious omission in the DOTS strategy. A critical review of the intellectual roots of the current approach is an important first step in furthering a conversation about how to close a number of important gaps in the global struggle against tuberculosis.

Key Points• HDACi-mediated differentiation therapy is a potent and molecularly rational treatment strategy in t(8;21) AML.Epigenetic modifying enzymes such as histone deacetylases (HDACs), p300, and PRMT1 are recruited by AML1/ETO, the pathogenic protein for t(8;21) acute myeloid leukemia (AML), providing a strong molecular rationale for targeting these enzymes to treat this disease. Although early phase clinical assessment indicated that treatment with HDAC inhibitors (HDACis) may be effective in t(8;21) AML patients, rigorous preclinical studies to identify the molecular and biological events that may determine therapeutic responses have not been performed. Using an AML mouse model driven by expression of AML1/ ETO9a (A/E9a), we demonstrated that treatment of mice bearing t(8;21) AML with the HDACi panobinostat caused a robust antileukemic response that did not require functional p53 nor activation of conventional apoptotic pathways. Panobinostat triggered terminal myeloid differentiation via proteasomal degradation of A/E9a. Importantly, conditional A/E9a deletion phenocopied the effects of panobinostat and other HDACis, indicating that destabilization of A/E9a is critical for the antileukemic activity of these agents. (Blood. 2014;123(9):1341-1352

Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major antitumor responses to histone deacetylase inhibitors (HDACi). These compounds can also mediate immune-modulatory effects that may contribute to their anticancer effects. However, HDACi can also induce anti-inflammatory, and potentially immunosuppressive, outcomes. We therefore sought to clarify the role of the immune system in mediating the efficacy of HDACi in a physiologic setting, using preclinical, syngeneic murine models of hematologic malignancies and solid tumors. We showed an intact immune system was required for the robust anticancer effects of the HDACi vorinostat and panobinostat against a colon adenocarcinoma and two aggressive models of leukemia/lymphoma. Importantly, although HDACi-treated immunocompromised mice bearing established lymphoma succumbed to disease significantly earlier than tumor bearing, HDACitreated wild-type (WT) mice, treatment with the conventional chemotherapeutic etoposide equivalently enhanced the survival of both strains. IFN-g and tumor cell signaling through IFN-gR were particularly important for the anticancer effects of HDACi, and vorinostat and IFN-g acted in concert to enhance the immunogenicity of tumor cells. Furthermore, we show that a combination of vorinostat with a-galactosylceramide (a-GalCer), an IFN-g-inducing agent, was significantly more potent against established lymphoma than vorinostat treatment alone. Intriguingly, B cells, but not natural killer cells or CD8 þ T cells, were implicated as effectors of the vorinostat antitumor immune response. Together, our data suggest HDACi are immunostimulatory during cancer treatment and that combinatorial therapeutic regimes with immunotherapies should be considered in the clinic. Cancer Res; 73(24); 7265-76. Ó2013 AACR.