Zenith abstract to be presented at AACR meeting 11/30
posted on
Nov 18, 2016 12:44PM
Zenith's BET Inhibitor ZEN-3694 is Currently Being Evaluated in Multiple Oncology Clinical Trials
11/30: Zenith presents at EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium in Munich. Title: The investigational drug ZEN-3694, a novel BET-bromodomain inhibitor, inhibits multiple tumor immune escape mechanisms and has the potential to combine with immunotherapies.
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 and lung cancer. 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, ZEN-3694 downregulates the checkpoints B7-H3 and PD-L1, and upregulates the MHC Class IA 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 selectively represses Th2 cytokines more potently than Th1 cytokines thus potentially shifting the T cells to a tumor killing response. ZEN-3694 also targets several recently identified markers of intrinsic PD-1 resistance. 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.