S. Attwell, Karen Norek, R. Jahagirdar
Dec 1, 2016
Citations
0
Influential Citations
1
Citations
Quality indicators
Journal
European Journal of Cancer
Abstract
ZEN-3694 is an orally bioavailable, potent inhibitor of both bromodomains of the Bromodomain and Extra-Terminal domain (BET) proteins. In vitro, ZEN-3694 has demonstrated strong activity against cell lines representing a broad range of solid tumor and hematological malignancies with submicromolar potency, and shows in vivo activity in several xenograft models, including prostate, breast, colon and AML. ZEN-3694 is currently in phase 1 clinical trials for metastatic castration resistant prostate cancer patients who have progressed on enzalutamide and/or abiraterone. Immunotherapies targeting the PD1/PD-L1 axis have shown remarkable durable efficacy for many cancers, but still, the majority of patients do not respond to these therapies alone, and therefore there is a need to identify combination agents which will increase the response rate. Here we show that ZEN-3694 targets many pathways which suppress the anti-tumor immune response. In solid tumor cell lines representing a variety of malignancies, ZEN3694 downregulates the checkpoints B7H3 and PD-L1, and upregulates the MICA antigen. In activated CD8+ T cells, ZEN-3694 targets multiple checkpoint receptors known to be involved in tumor escape. ZEN-3694 also inhibits the differentiation and function of Regulatory T cells (Tregs), and strongly inhibits the suppressive cytokines/chemokines IL-10 and CCL2. ZEN-3694 also targets several recently identified markers of intrinsic PD-1 resistance, and inhibits the angiogenic factor VegF. Effects on these various markers of immunomodulation are being confirmed in our current phase I study. Immunomodulatory effects were also measured in vivo. In an MC-38 colon cancer syngeneic xenograft model, the addition of ZEN-3694 increases the efficacy of anti-PD1 in tumor growth inhibition. The ZEN-3694 treated mice showed a significant increase in IFNg+ CD8 T cells in the draining lymph nodes, as well as an increase in CD8+ tumor infiltrating lymphocytes (TILS) in the tumor. Analysis of the tumors showed a decrease in markers of myeloid suppressive cells. Taken together these data suggest that ZEN-3694 targets several mechanisms of resistance to PD1 therapy, and has the potential to synergize with a variety of cancer immunotherapies. The Bromodomain and Extra-Terminal domain (BET) family of proteins BRD2, BRD3, BRD4, and BRDT are epigenetic readers that bind via their tandem bromodomains (BD1 & BD2) to acetylated lysines in histones and promote gene transcription. Tumor type specific super-enhancers associated with key oncogenes involved in tumor pathogenesis have been identified in hematological as well as solid tumor malignancies1,2. Inhibition of BET proteins results in their displacement from super-enhancers leading to down regulation of key oncogenic programs, including members of the MYC and BCL-2 families1. Additionally, BET inhibitors (BETi) target pathways involved in metastasis, such as the NF-kB and Wnt5a pathways3,4. BET inhibitors have been demonstrated to inhibit proliferation and suppress tumorigenicity in numerous solid and hematological malignancies. Although PD1 antibodies have shown remarkable and durable efficacy in a portion of cancers, a variety of immune mechanisms contribute to both innate and acquired resistance in the majority of patients. These include upregulation of alternate tumor and T cell checkpoint receptors, recruitment of suppressive cells which dampen the T cell response, and tumor mechanisms to decrease immune recognition. Here we show that BET inhibitors have an additional unique mechanism of action: they inhibit multiple complementary mechanisms of tumor immune escape, which suggest that they could synergize with immunotherapies. Background Summary The investigational drug ZEN-3694, a novel BET-bromodomain inhibitor, inhibits multiple tumor immune escape mechanisms and has the potential to combine with immunotherapies Sarah Attwell1, Karen Norek1, Ravi Jahagirdar1, Cyrus Calosing1, Sanjay Lakhotia2, Eric Campeau1, Henrik C. Hansen1 1Zenith Epigenetics, Suite 300, 4820 Richard Road SW, Calgary AB, Canada and 2Suite 4010, 44 Montgomery St. San Francisco CA, USA,